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The invention provides methods and compositions for treating conditions
mediated by various kinases wherein derivatives of amide compounds are
employed. The invention also provides methods of using the compounds
and/or compositions in the treatment of a variety of diseases and
unwanted conditions in subjects.

1. A compound corresponding to Formula (I): 353wherein: each Z is
independently C, CR.sub.4, N, NR.sub.4, O, or S, provided that no more
than two Z's are heteroatoms and wherein no two adjacent Z's are O or S,
where R.sub.4 is H, substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl or
substituted or unsubstituted aryl; each R.sub.1 is independently H,
halogen, substituted or unsubstituted alkyl, substituted or unsubstituted
alkoxy, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sub.c, --OC(O)R.sub.c,
--NO.sub.2, --N(R.sub.c).sub.2, --SR.sub.c, S(O).sub.jR.sub.c where j is
1 or 2, --NR.sub.cC(O)R.sub.c, --C(O)N(R.sub.c).sub.2,
--C(O).sub.2R.sub.c, or --C(O)R.sub.c; or two adjacent R.sub.1's, are
taken together, to form a substituted or unsubstituted aryl or
heteroaryl; where each R.sub.c is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl; and K
is 354Y is O or S; each R.sub.2 is independently H, halogen, substituted
or unsubstituted alkyl, --OH, substituted or unsubstituted alkoxy,
--OC(O)R.sub.3, --NO.sub.2, --N(R.sub.3).sub.2, --SR.sub.3,
--NR.sub.cC(O), --C(O)N(R.sub.c).sub.2, --C(O).sub.2R.sub.c, or
--C(O)R.sub.c; each R.sub.3 is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; and each n is independently 0,
1, 2, 3 or 4; or an active metabolite, or a pharmaceutically acceptable
prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, corresponding to Formula (II): 355

3. The compound of claim 2, corresponding to Formula (III): 356wherein:
Z.sub.1 is CR.sub.4 or N; and Z.sub.2 is O or S.

4. The compound of claim 3, corresponding to Formula (IV): 357wherein: L
is a linker selected from the group consisting of --C(O)NH--,
-(substituted or unsubstituted alkylene)-, -(substituted or unsubstituted
alkenylene)-, --C(O)NH(substituted or unsubstituted alkylene)-,
--C(O)NH(substituted or unsubstituted alkenylene)-, --O(substituted or
unsubstituted alkylene)-, --N(substituted or unsubstituted alkylene)-,
--C(O)--, --NH--, --O--, --S--, --NHC(O)(substituted or unsubstituted
alkylene)-, --NHC(O)(substituted or unsubstituted alkylene)-, a covalent
bond, --C(O)(substituted or unsubstituted alkenylene)-,
--C(O)(substituted or unsubstituted alkylene)-, --NHC(O)(substituted or
unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH--,
--NHC(O)(substituted or unsubstituted alkenylene)-; and T is a mono-,
bi-, or tricyclic, substituted or unsubstituted cycloalkyl, heterocyclyl,
aryl, or heteroaryl.

5. The compound of claim 4, wherein T corresponds to Formula (V):
358wherein A is a substituted or unsubstituted five or six-membered aryl
or heteroaryl; and B is a substituted or unsubstituted five or
six-membered arylene or heteroarylene, wherein A and B together form a
fused two-ring moiety.

12. The compound of claim 11, selected from the group consisting of: 362

13. The compound of claim 4, corresponding to: 363

14. The compound of claim 4, corresponding to Formula (VII): 364wherein:
each of X.sub.1-X.sub.5 is independently C, CR, N, NR, S, or O, wherein
no more than three of X.sub.1-X.sub.5 is a heteroatom and no 2 adjacent
ring atoms are O; and each R is independently H, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, --OR.sub.d, --OC(O)R.sub.d, --NO.sub.2, --N(R.sub.d).sub.2,
--SR.sub.d, S(O).sub.jR.sub.d where j is 1 or 2, --NR.sub.dC(O)R.sub.d,
--C(O)N(R.sub.d).sub.2, --C(O).sub.2R.sub.d, or --C(O)R.sub.d; or two
adjacent R's, are taken together, to form a substituted or unsubstituted
aryl or heteroaryl; where each R.sub.d is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl.

15. The compound of claim 14, corresponding to Formula (VIII): 365

16. The compound of claim 15, wherein L is a covalent bond, --C(O)NH--,
--OCH.sub.2--, or --OCH.sub.2CH.sub.2--.

17. The compound of claim 15, wherein 366is selected from the group
consisting of: 367

18. The compound of claim 17 selected from the group consisting of:
368369

19. The compound of claim 4, corresponding to Formula (IX): 370wherein:
371is selected from the group consisting of: (a) L is selected from the
group consisting of --O(substituted or unsubstituted alkylene)-, and
--C(O)(substituted or unsubstituted alkenylene)-; and each of
X.sub.1-X.sub.5 is independently CR, N--O, or N, wherein no more than two
of X.sub.1-X.sub.5 is N, where each R is independently H, halogen,
substituted or unsubstituted alkyl, --OH, substituted or unsubstituted
alkoxy, --OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2, --SR.sub.c,
--NR.sub.cC(O)R.sub.c, or --C(O)R.sub.c; where each R.sub.c is
independently H, substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; (b) L is --NH--; each of
X.sub.1, X.sub.2, X.sub.4, and X.sub.5 is independently CR or N; and
X.sub.3 is independently CR.sub.6 or N, wherein no more than two of
X.sub.1-X.sub.5 is N, where R.sub.6 is selected from the group consisting
of H, halogen, substituted or unsubstituted alkyl, substituted alkoxy,
--C(O)R.sub.c, --OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2, and
--SR.sub.c; where each Rc is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl; (c) L
is --NH--; each of X.sub.1, X.sub.3, and X.sub.5 is independently CR or
N; and each of X.sub.2 and X.sub.4 is independently CR.sub.7 or N,
wherein no more than two of X.sub.1-X.sub.5 is N; where R.sub.7 is
selected from the group consisting of H, halogen, unsubstituted alkyl,
--OH, substituted or unsubstituted alkoxy, --C(O)R.sub.c, --OC(O)R.sub.c,
--NO.sub.2, --N(R.sub.c).sub.2, --SR.sub.c, and alkyl substituted with
alkoxy, halogen, aryl, heteroaryl, amine, --C(O)R.sub.c, --OC(O)R.sub.c,
--NO.sub.2, --N(R.sub.c).sub.2, or --SR.sub.c; where each Rc is
independently H, substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; and (d) L is --C(O)NH--; each of
X.sub.1, X.sub.2, X.sub.4, and X.sub.5 is independently CR or N; and
X.sub.3 is independently CR.sub.8 or N, wherein no more than two of
X.sub.1-X.sub.5 is N, and when X.sub.3 is N, at least one of X.sub.1,
X.sub.2, X.sub.3, or X.sub.5 is not CH, where R.sub.8 is selected from
the group consisting of H, halogen, substituted or unsubstituted alkyl,
--OR.sub.c, substituted or unsubstituted alkoxy, --C(O)R.sub.c,
--OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2, and --SR.sub.c, where
each Rc is independently H, substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
aryl, or substituted or unsubstituted heteroaryl.

23. The compound of claim 22, selected from the group consisting of:
374375

24. The compound of claim 20, corresponding to Formula (XII): 376

25. The compound of claim 24, corresponding to: 377

26. The compound of claim 20, corresponding to Formula (XIII): 378

27. The compound of claim 26, corresponding to: 379

28. The compound of claim 20, corresponding to Formula (XIV): 380

29. The compound of claim 28, selected from the group consisting of: 381

30. The compound of claim 20, corresponding to Formula (XV): 382

31. The compound of claim 30, corresponding to: 383

32. The compound of claim 20, corresponding to Formula (XVI): 384

33. The compound of claim 32, wherein L is a linker selected from the
group consisting of --NHC(O)--, --O(C.sub.1-C.sub.3 alkyl),
--NHC(O)CH.sub.2SCH.sub.2C(O)NH--, --CHCHCH.sub.2O--,
--CH.sub.2CH.sub.2--, --NHC(O)--(C.sub.1-C.sub.4 alkene),
--NHC(O)--(C.sub.1-C.sub.3 alkyl), and --CH.sub.2CH.sub.2C(O)NH--.

34. The compound of claim 33, selected from the group consisting of:
385386387

35. The compound of claim 2, corresponding to: 388

36. The compound of claim 4, corresponding to: 389

37. The compound of claim 4, corresponding to Formula (XVII): 390wherein:
L is a linker selected from the group consisting of --C(O)NH--,
-(substituted or unsubstituted alkylene)-, -(substituted or unsubstituted
alkenylene)-, --C(O)NH(substituted or unsubstituted alkylene)-,
--C(O)NH(substituted or unsubstituted alkenylene)-, --O(substituted or
unsubstituted alkylene)-, --N(substituted or unsubstituted alkylene)-,
--C(O)--, --NH--, --O--, --S--, --NHC(O)(substituted or unsubstituted
alkylene)-, --NHC(O)(substituted or unsubstituted alkylene)-, a covalent
bond, --C(O)(substituted or unsubstituted alkenylene)-,
--C(O)(substituted or unsubstituted alkylene)-, --NHC(O)(substituted or
unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH--,
--NHC(O)(substituted or unsubstituted alkenylene)-; each of
X.sub.1-X.sub.5 is independently C, CR, N--O, or N, wherein no more than
two of X--X.sub.5 is N; where each R is independently H, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sub.d, --OC(O)R.sub.d, --NO.sub.2,
--N(R.sub.d).sub.2, --SR.sub.d, S(O).sub.jR.sub.d where j is 1 or 2,
--NR.sub.dC(O)R.sub.d, --C(O)N(R.sub.d).sub.2, --C(O).sub.2R.sub.d, or
--C(O)R.sub.d; or two adjacent R's, are taken together, to form a
substituted or unsubstituted aryl or heteroaryl; where each R.sub.d is
independently H, substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl.

38. The compound of claim 4, corresponding to Formula (XVIII):
391wherein: 392is selected from the group consisting of: (a) each of L
and L.sub.1 is independently a linker selected from the group consisting
of a covalent bond, --O(substituted or unsubstituted alkylene)-, --S--,
-(substituted or unsubstituted alkylene)-, --C(O)--, and --N(substituted
or unsubstituted alkylene)-; U is a substituted or unsubstituted
cycloalkyl, aryl, or heteroaryl; and V is a substituted or unsubstituted
cycloalkylene, heterocyclene, arylene, or heteroarylene; (b) L is a
linker selected from the group consisting of a covalent bond,
--O(substituted or unsubstituted alkylene)-, --S--, -(substituted or
unsubstituted alkylene)-, --O--, --NH--, --C(O)--, --C(O)NH--, and
--N(substituted or unsubstituted alkylene)-; L.sub.1 is a linker selected
from the group consisting of a covalent bond, --O(substituted or
unsubstituted alkylene)-, --S--, -(substituted or unsubstituted
alkylene)-, --O--, --NH--, --C(O)--, and --N(substituted or unsubstituted
alkylene)-; U is selected from the group consisting of: (i) substituted
or unsubstituted cycloalkyl; (ii) unsubstituted aryl; (iii) aryl
substituted at any position with --Cl, --I, substituted or unsubstituted
alkyl, --OH, substituted or unsubstituted alkoxy, --OC(O)R.sub.3,
--NO.sub.2, --N(R.sub.3).sub.2, --SR.sub.3, --C(O)R.sub.3, where R.sub.3
is H, --OH, --N(R.sub.3).sub.2, or substituted or unsubstituted alkoxy,
and where R.sub.3 is H or substituted or unsubstituted alkyl; and (iv)
substituted or unsubstituted heteroaryl, except pyridinyl; V is a
substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or
heteroarylene; and (c) L is a linker selected from the group consisting
of a covalent bond, --O(substituted or unsubstituted alkylene)-, --S--,
-(substituted or unsubstituted alkylene)-, --O--, --NH--, --C(O)--,
--C(O)NH--, and --N(substituted or unsubstituted alkylene)-; L.sub.1 is a
linker selected from the group consisting of a covalent bond,
--O(substituted or unsubstituted C.sub.2-C.sub.5 alkylene)-, --S--,
-(substituted or unsubstituted alkylene)-, --O--, --NH--, --C(O)--,
--C(O)NH--, and --N(substituted or unsubstituted alkylene)-; U is
selected from the group consisting of substituted or unsubstituted
cycloalkyl; substituted aryl; and substituted or unsubstituted
heteroaryl; and V is a substituted or unsubstituted cycloalkylene,
heterocyclene, arylene, or heteroarylene.

39. The compound of claim 38, corresponding to Formula (XIX): 393

40. The compound of claim 39, wherein L.sub.1 is a bond; and L is a bond
or --C(O)NH--.

41. The compound of claim 40, wherein U is substituted or unsubstituted
phenyl, thiazolyl, or pyridinyl; and V is substituted or unsubstituted
piperidinylene, thiazolylene, imidazolylene, or thiophenylene.

42. The compound of claim 41, selected from the group consisting of: 394

43. The compound of claim 39, corresponding to Formula (XX): 395

44. The compound of claim 43, wherein L.sub.1 is a bond, --CH.sub.2O--,
--N(CH.sub.3)-- or --O--; and L is --CH.sub.2O-- or --NHC(O)--.

46. The compound of claim 45, selected from the group consisting of: 396

47. The compound of claim 39, corresponding to Formula (XXI): 397

48. The compound of claim 47, wherein L.sub.1 is a --NH-- or --O--; and L
is --NHC(O)--.

49. The compound of claim 48, wherein U is substituted or unsubstituted
pyrmidyl.

50. The compound of claim 49, selected from the group consisting of: 398

51. The compound of claim 39, corresponding to: 399

52. The compound of claim 4, corresponding to Formula (XXII): 400wherein:
L is a linker selected from the group consisting of --C(O)NH--,
-(substituted or unsubstituted alkylene)-, -(substituted or unsubstituted
alkenylene)-, --C(O)NH(substituted or unsubstituted alkylene)-,
--C(O)NH(substituted or unsubstituted alkenylene)-, --O(substituted or
unsubstituted alkylene)-, --N(substituted or unsubstituted alkylene)-,
--C(O)--, --NH--, --O--, --S--, --NHC(O)(substituted or unsubstituted
alkylene)-, --NHC(O)(substituted or unsubstituted alkylene)-, a covalent
bond, --C(O)(substituted or unsubstituted alkenylene)-,
--C(O)(substituted or unsubstituted alkylene)-, --NHC(O)(substituted or
unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH--,
--NHC(O)(substituted or unsubstituted alkenylene)-; U is a substituted or
unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; and V is a
substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or
heteroarylene.

53. A method of modulating p38 kinase, said method comprising
administering an effective amount of a compound, corresponding to Formula
(IA): 401wherein: M is a substituted or unsubstituted aryl or
heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and K
is 402Y is O or S; each R.sub.2 is independently H, halogen, substituted
or unsubstituted alkyl, --OH, substituted or unsubstituted alkoxy,
--OC(O)R.sub.3, --NO.sub.2, --N(R.sub.3).sub.2, --SR.sub.3,
--NR.sub.3C(O)R.sub.3, --C(O)N(R.sub.3).sub.2, --C(O).sub.2R.sub.3, or
--C(O)R.sub.3; each R.sub.3 is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; and each n is independently 0,
1, 2, 3 or 4; or an active metabolite, or a pharmaceutically acceptable
prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

54. The method of claim 53, wherein said compound corresponds to to
Formula (I): 403wherein: each Z is independently C, CR.sub.4, N,
NR.sub.4, O or S, provided that no more than two Z's are heteroatoms and
wherein no two adjacent Z's are O or S, where R.sub.4 is H, substituted
or unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heteroaryl or substituted or unsubstituted
aryl; and each R.sub.1 is independently H, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, --OR.sub.c, --OC(O)R, --NO.sub.2, --N(R.sub.c).sub.2,
--SR.sub.c, S(O).sub.jR.sub.c where j is 1 or 2, --NR.sub.cC(O)R.sub.c,
--C(O)N(R.sub.c).sub.2, --C(O).sub.2R.sub.c, or --C(O)R.sub.c; or two
adjacent R.sub.1's, are taken together, to form a substituted or
unsubstituted aryl or heteroaryl; where each R.sub.c is independently H,
substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl.

55. The method of claim 53, wherein said compound corresponds to Formula
(IV): 404wherein: L is a linker selected from the group consisting of
--C(O)NH--, -(substituted or unsubstituted alkylene)-, -(substituted or
unsubstituted alkenylene)-, --C(O)NH(substituted or unsubstituted
alkylene)-, --C(O)NH(substituted or unsubstituted alkenylene)-,
--O(substituted or unsubstituted alkylene)-, --N(substituted or
unsubstituted alkylene)-, --C(O)--, --NH--, --O--, --S--,
--NHC(O)(substituted or unsubstituted alkylene)-, --NHC(O)(substituted or
unsubstituted alkylene)-, a covalent bond, --C(O)(substituted or
unsubstituted alkenylene)-, --C(O)(substituted or unsubstituted
alkylene)-, --NHC(O)(substituted or unsubstituted alkylene)S(substituted
or unsubstituted alkylene)C(O)NH--, --NHC(O)(substituted or unsubstituted
alkenylene)-; T is a mono-, bi-, or tricyclic, substituted or
unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; Z.sub.1 is
CR.sub.4 or N; and Z.sub.2 is O or S.

56. The method of claim 55, wherein said compound corresponds to Formula
(VI): 405wherein A is a substituted or unsubstituted five or
six-membered aryl, heteroaryl, or heterocyclyl; and B is a substituted or
unsubstituted five or six-membered arylene, heteroarylene, or
heterocyclene, wherein A and B together form a fused two-ring moiety.

57. The method of claim 56, wherein L of said compound is --NH-- or
--C(O)NH--.

58. The method of claim 57, wherein B of said compound is substituted or
unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene,
thiophenylene, or imidazolylene.

59. The method of claim 58, wherein said compound is selected from the
group consisting of: 406

60. The method of claim 53, wherein said compound is selected from the
group consisting of: 407

61. The method of claim 53, wherein said compound corresponds to (XXIII):
408wherein: L is a linker selected from the group consisting of
--C(O)NH--, -(substituted or unsubstituted alkylene)-, -(substituted or
unsubstituted alkenylene)-, --C(O)NH(substituted or unsubstituted
alkylene)-, --C(O)NH(substituted or unsubstituted alkenylene)-,
--O(substituted or unsubstituted alkylene)-, --N(substituted or
unsubstituted alkylene)-, --C(O)--, --NH--, --O--, --S--,
--NHC(O)(substituted or unsubstituted alkylene)-, --NHC(O)(substituted or
unsubstituted alkylene)-, a covalent bond, --C(O)(substituted or
unsubstituted alkenylene)-, --C(O)(substituted or unsubstituted
alkylene)-, --NHC(O)(substituted or unsubstituted alkylene)S(substituted
or unsubstituted alkylene)C(O)NH--, --NHC(O)(substituted or unsubstituted
alkenylene)-; T is optional, and when present, is a mono-, bi-, or
tricyclic, substituted or unsubstituted heterocyclyl, aryl, or
heteroaryl; Z.sub.3 is NR.sub.4, O, or S; and Z.sub.4 is N or CR.sub.4.

62. The method of claim 61, wherein said compound is selected from the
group consisting of: 409

63. A method of modulating MKNK2 kinase, said method comprising
administering an effective amount of a compound corresponding to Formula
(IA): 410wherein: M is a substituted or unsubstituted aryl or
heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and K
is 411Y is O or S; each R.sub.2 is independently H, halogen, substituted
or unsubstituted alkyl, --OH, substituted or unsubstituted alkoxy,
--OC(O)R.sub.3, --NO.sub.2, --N(R.sub.3).sub.2, --SR.sub.3,
--NR.sub.3C(O)R.sub.3, --C(O)N(R.sub.3).sub.2, --C(O).sub.2R.sub.3, or
--C(O)R.sub.3; each R.sub.3 is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; and each n is independently 0,
1, 2, 3 or 4; or an active metabolite, or a pharmaceutically acceptable
prodrug, pharmaceutically acceptable salt or solvate thereof.

64. The method of claim 63, wherein said compound corresponds to Formula
(I): 412wherein: each Z is independently C, CR.sub.4, N, NR.sub.4, O or
S, provided that no more than two Z's are heteroatoms and wherein no two
adjacent Z's are O or S, where R.sub.4 is H, substituted or unsubstituted
alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heteroaryl or substituted or unsubstituted aryl; and each
R.sub.1 is independently H, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --OR.sub.c,
--OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2, --SR.sub.c,
S(O).sub.jR.sub.c where j is 1 or 2, --NR.sub.cC(O)R.sub.c,
--C(O)N(R.sub.c).sub.2, --C(O).sub.2R.sub.c, or --C(O)R.sub.c; or two
adjacent R.sub.1's, are taken together, to form a substituted or
unsubstituted aryl or heteroaryl; where each R.sub.c is independently H,
substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl.

65. The method of claim 64, wherein said compound corresponds to Formula
(IV): 413wherein: L is a linker selected from the group consisting of
--C(O)NH--, -(substituted or unsubstituted alkylene)-, -(substituted or
unsubstituted alkenylene)-, --C(O)NH(substituted or unsubstituted
alkylene)-, --C(O)NH(substituted or unsubstituted alkenylene)-,
--O(substituted or unsubstituted alkylene)-, --N(substituted or
unsubstituted alkylene)-, --C(O)--, --NH--, --O--, --S--,
--NHC(O)(substituted or unsubstituted alkylene)-, --NHC(O)(substituted or
unsubstituted alkylene)-, a covalent bond, --C(O)(substituted or
unsubstituted alkenylene)-, --C(O)(substituted or unsubstituted
alkylene)-, --NHC(O)(substituted or unsubstituted alkylene)S(substituted
or unsubstituted alkylene)C(O)NH--, --NHC(O)(substituted or unsubstituted
alkenylene)-; T is a mono-, bi-, or tricyclic, substituted or
unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; Z.sub.1 is
CR.sub.4 or N; and Z.sub.2 is O or S.

66. The method of claim 65, wherein said compound corresponds to Formula
(VI): 414wherein A is a substituted or unsubstituted five or
six-membered aryl, heteroaryl, or heterocyclyl; and B is a substituted or
unsubstituted five or six-membered arylene, heteroarylene, or
heterocyclene, wherein A and B together form a fused two-ring moiety.

67. The method of claim 66, wherein A of said compound is substituted or
unsubstituted pyridinyl, phenyl, thiophenyl, tolyl, or imidazolyl; and B
of said compound is substituted or unsubstituted phenylene, pyridinylene,
pyrimidinylene, pyridazinylene, thiophenylene, or imidazolylene.

68. The method of claim 67, wherein said compound is selected from the
group consisting of: 415

69. The method of claim 65, wherein said compound corresponds to Formula
(XVII): 416wherein: each of X.sub.1-X.sub.5 is independently C, CR,
N--O, or N, wherein no more than two of X.sub.1-X.sub.5 is N; where each
R is independently H, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --OR.sub.d,
--OC(O)R.sub.d, --NO.sub.2, --N(R.sub.d).sub.2, --SR.sub.d,
S(O).sub.jR.sub.d where j is 1 or 2, --NR.sub.dC(O)R.sub.d,
--C(O)N(R.sub.d).sub.2, --C(O).sub.2R.sub.d, or --C(O)R.sub.d; or two
adjacent R's, are taken together, to form a substituted or unsubstituted
aryl or heteroaryl; where each R.sub.d is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl.

72. The method of claim 71, wherein said compound is selected from the
group consisting of: 418

73. The method of claim 63, wherein said compound is selected from the
group consisting of: 419

74. A method of modulating STK10 kinase, said method comprising
administering an effective amount of a compound corresponding to Formula
(IA): 420wherein: M is a substituted or unsubstituted aryl or
heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and K
is 421Y is O or S; each R.sub.2 is independently H, halogen, substituted
or unsubstituted alkyl, --OH, substituted or unsubstituted alkoxy,
--OC(O)R.sub.3, --NO.sub.2, --N(R.sub.3).sub.2, --SR.sub.3,
--NR.sub.3C(O)R.sub.3, --C(O)N(R.sub.3).sub.2, --C(O).sub.2R.sub.3, or
--C(O)R.sub.3; each R.sub.3 is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; and each n is independently 0,
1, 2, 3 or 4; or an active metabolite, or a pharmaceutically acceptable
prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

75. The method of claim 74, wherein said compound corresponds to to
Formula (I): 422wherein: each Z is independently C, CR.sub.4, N,
NR.sub.4, O or S, provided that no more than two Z's are heteroatoms and
wherein no two adjacent Z's are O or S, where R.sub.4 is H, substituted
or unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heteroaryl or substituted or unsubstituted
aryl; and each R.sub.1 is independently H, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, --OR.sub.c, --OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2,
--SR.sub.c, S(O).sub.jR.sub.c where j is 1 or 2, --NR.sub.cC(O)R.sub.c,
--C(O)N(R.sub.c).sub.2, --C(O).sub.2R.sub.c, or --C(O)R.sub.c; or two
adjacent R.sub.1's, are taken together, to form a substituted or
unsubstituted aryl or heteroaryl; where each R.sub.c is independently H,
substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl.

76. The method of claim 75, wherein said compound corresponds to Formula
(IV): 423wherein: L is a linker selected from the group consisting of
--C(O)NH--, -(substituted or unsubstituted alkylene)-, -(substituted or
unsubstituted alkenylene)-, --C(O)NH(substituted or unsubstituted
alkylene)-, --C(O)NH(substituted or unsubstituted alkenylene)-,
--O(substituted or unsubstituted alkylene)-, --N(substituted or
unsubstituted alkylene)-, --C(O)--, --NH--, --O--, --S--,
--NHC(O)(substituted or unsubstituted alkylene)-, --NHC(O)(substituted or
unsubstituted alkylene)-, a covalent bond, --C(O)(substituted or
unsubstituted alkenylene)-, --C(O)(substituted or unsubstituted
alkylene)-, --NHC(O)(substituted or unsubstituted alkylene)S(substituted
or unsubstituted alkylene)C(O)NH--, --NHC(O)(substituted or unsubstituted
alkenylene)-; T is a mono-, bi-, or tricyclic, substituted or
unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; Z.sub.1 is
CR.sub.4 or N; and Z.sub.2 is O or S.

77. The method of claim 76, wherein said compound corresponds to Formula
(VI): 424wherein A is a substituted or unsubstituted five or
six-membered aryl, heteroaryl, or heterocyclyl; and B is a substituted or
unsubstituted five or six-membered arylene, heteroarylene, or
heterocyclene, wherein A and B together form a fused two-ring moiety.

78. The method of claim 77, wherein L of said compound is --NH-- or a
covalent bond.

79. The method of claim 78, wherein B of said compound is substituted or
unsubstituted phenylene, pyridinylene, pyrimidinylene, pyridazinylene,
thiophenylene, or imidazolylene.

80. The method of claim 79, wherein said compound is selected from the
group consisting of: 425

81. A method of treating a cellular proliferative disorder, said method
comprising administering a therapeutically effective amount of a
compound, or pharmaceutically acceptable salt thereof, corresponding to
Formula (IA) 426wherein: M is a substituted or unsubstituted aryl or
heteroaryl; N is a substituted or unsubstituted aryl or heteroaryl; and K
is 427Y is O or S; each R.sub.2 is independently H, halogen, substituted
or unsubstituted alkyl, --OH, substituted or unsubstituted alkoxy,
--OC(O)R.sub.3, --NO.sub.2, --N(R.sub.3).sub.2, --SR.sub.3,
--NR.sub.3C(O)R.sub.3, --C(O)N(R.sub.3).sub.2, --C(O).sub.2R.sub.3, or
--C(O)R.sub.3; each R.sub.3 is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; and each n is independently 0,
1, 2, 3 or 4; or an active metabolite, or a pharmaceutically acceptable
prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.

82. The method of claim 81, wherein said compound corresponds to Formula
(I): 428wherein: each Z is independently C, CR.sub.4, N, NR.sub.4, O or
S, provided that no more than two Z's are heteroatoms and wherein no two
adjacent Z's are O or S, where R.sub.4 is H, substituted or unsubstituted
alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heteroaryl or substituted or unsubstituted aryl; and each
R.sub.1 is independently H, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --OR.sub.c,
--OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2, --SR.sub.c,
S(O).sub.jR.sub.c where j is 1 or 2, --NR.sub.cC(O)R.sub.c,
--C(O)N(R.sub.c).sub.2, --C(O).sub.2R.sub.c, or --C(O)R.sub.c; or two
adjacent R.sub.1's, are taken together, to form a substituted or
unsubstituted aryl or heteroaryl; where each R.sub.c is independently H,
substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl.

[0002] Protein kinases (PKs) play a role in signal transduction pathways
regulating a number of cellular functions, such as cell growth,
differentiation, and cell death. PKs are enzymes that catalyze the
phosphorylation of hydroxy groups on tyrosine, serine and threonine
residues of proteins, and can be conveniently broken down into two
classes, the protein tyrosine kinases (PTKs) and the serine-threonine
kinases (STKs). Growth factor receptors with PTK activity are known as
receptor tyrosine kinases. Protein receptor tyrosine kinases are a family
of tightly regulated enzymes, and the aberrant activation of various
members of the family is one of the hallmarks of cancer. The
protein-tyrosine kinase family, which includes Bcr-Abl tyrosine kinase,
can be divided into subgroups that have similar structural organization
and sequence similarity within the kinase domain. The members of the type
III group of receptor tyrosine kinases include the platelet-derived
growth factor (PDGF) receptors (PDGF receptors .alpha. and .beta.),
colony-stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), FLT-3, and
stem cell or steel factor receptor (c-kit). A more complete listing of
the known Protein receptor tyrosine kinases subfamilies is described in
Plowman et al., DN&P, 7(6):334-339 (1994), which is incorporated by
reference, including any drawings, as if fully set forth herein.
Furthermore, for a more detailed discussion of "non-receptor tyrosine
kinases", see Bolen, Oncogene, 8:2025-2031 (1993), which is incorporated
by reference, including any drawings, as if fully set forth herein.

[0003] Hematologic cancers, also known as hematologic or hematopoietic
malignancies, are cancers of the blood or bone marrow; including leukemia
and lymphoma. Acute myelogenous leukemia (AML) is a clonal hematopoietic
stem cell leukemia that represents .about.90% of all acute leukemias in
adults. See e.g., Lowenberg et al., N. Eng. J. Med. 341:1051-62 (1999).
While chemotherapy can result in complete remissions, the long term
disease-free survival rate for AML is about 14% with about 7,400 deaths
from AML each year in the United States. The single most commonly mutated
gene in AML is FLT3 kinase. See e.g., Abu-Duhier et al., Br. J. Haemotol.
111:190-05 (2000); Kiyoi et al., Blood 93:3074-80 (1999); Kottaridis et
al., Blood 98:1752-59 (2001); Stirewalt et al., Blood 97:3589-95 (2001).
Such mutations also indicate a poor prognosis for the patient.

[0004] The compounds provided by the present invention are urea
derivatives of substituted aryls and hetroaryls, e.g., isoxazoles,
pyrazoles and isothiazoles. Urea derivatives of pyrazoles have been
reported to be selective p38 kinase inhibitors by Dumas, J., et al.,
Bioorg. Medic. Chem. Lett. 10:2051-2054 (2000). Oxazoles and isopyrazoles
are suggested as blockers of cytokine production in WO 00/43384 published
27 Jul. 2000. Urea derivatives of isoxazole and pyrazoles are described
as inhibitors of RAF kinase in WO 99/32106 published 1 Jul. 1999. Such
compounds are also described as p38 kinase inhibitors by Dumas, J., et
al, Bioorg Medic. Chem. Lett. 10:2047-2050 (2000). These compounds are
also suggested as p38 kinase inhibitors in PCT publication WO 99/32111
published 1 Jul. 1999.

[0005] There remains a need for additional compounds that are effective in
inhibiting kinase activity. Given the complexities of signal transduction
with the redundancy and crosstalk between various pathways, the
identification of specific kinase inhibitors permits accurate targeting
with limited inhibition of other pathways, thus reducing the toxicity of
such inhibitory compounds.

SUMMARY OF THE INVENTION

[0006] The present invention provides compounds which modulate kinase
activity, and in some embodiments inhibit protein tyrosine kinases or a
specific kinase or kinase class. In some embodiments, the compositions
and methods for treating and preventing conditions and diseases, such as
cancer, hematologic malignancies, cardiovascular disease, inflammation or
multiple sclerosis. The compounds of the invention can be delivered alone
or in combination with additional agents, and are used for the treatment
and/or prevention of conditions and diseases. Unless otherwise stated,
each of the substituents is as previously defined.

[0007] Provided herein are compositions and methods for treating a disease
comprising administering to a subject in need thereof an effective amount
of a kinase modulating compound having the structure: 1

[0017] Provided herein are compositions and methods for treating a disease
comprising administering to a subject in need thereof an effective amount
of a kinase modulating compound having the structure: 2

[0018] wherein:

[0019] (a) X.sub.b and Y.sub.b are independently selected from O, N,
NR.sub.c1, and CR.sub.c, wherein R.sub.c1 is a suitable substituent
selected from hydrogen; alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl unsubstituted or substituted with one,
two, or three suitable substituents, wherein X.sub.b and Y.sub.b are not
both oxygen;

[0040] Provided herein are compositions and methods for treating a disease
comprising administering to a subject in need thereof an effective amount
of a kinase modulating compound having the following structure: 7

[0050] (iii) T.sub.1 and T.sub.2 are each independently selected from
CR.sub.w and N, where R.sub.w is a suitable substituent selected from
hydrogen; halogens; --CN; and --NO.sub.2; and unsubstituted alkyl,
unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl,
unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and
unsubstituted heteroaryl, or two or more substituents cyclize to form a
fused or spiro polycyclic cycloalkyl, heterocycloalkyl, aryl, or
heteroaryl group;

[0052] Compositions and methods of Formulas A-G are provided wherein
X.sub.b is O and Y.sub.b is N and/or X.sub.b is N and Y.sub.b is O;
and/or R.sub.2a, R.sub.2g, R.sub.3a, R.sub.3g, R.sub.4a and R.sub.4g are
each hydrogen; and/or R.sub.1b, R.sub.1c, and R.sub.1d are each an
unsubstituted or substitued t-butyl and R.sub.2b and R.sub.2g are
hydrogen; and/or W.sub.a is O; and/or Z.sub.a is C(O)NH or NHC(O); and/or
n is 0. In various embodiments, T.sub.1 is N and T.sub.2 is N or T.sub.1
is N and T.sub.2 is CH. In other embodiments, Ar.sub.2 is: 9

[0056] Compositions and methods of Formulas A-G are provided herein
wherein R.sub.8g and R.sub.9g are each independently selected from the
group consisting of hydrogen; halogens; --CN; and --NO.sub.2; and alkyl,
alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, --(CH.sub.2).sub.zCN where z is a whole
integer from 0 to 4, --OH, --C(O)H, --OC(O)H, --C(O)OH, --NH.sub.2,
--C(O)NH.sub.2, --NHC(O), --OC(O)NH.sub.2, --NHC(O)H, --NHC(O)OH groups
unsubstituted or substituted with one, two or three suitable substituents
independently selected from the group consisting of halogens,
unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl,
unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted
heterocycloalkyl, and unsubstituted heteroaryl, or two or more
substituents cyclize to form a fused or spiro polycyclic cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl group.

[0057] Compositions and methods of Fomulas A-G are provided herein wherein
each R.sub.5c is a suitable substituent independently selected from the
group consisting of halogens; --CN;

[0059] Compositions and methods of Formula A are provided herein wherein
Ar.sub.3 is a 5-membered aryl, heteroaryl, heterocylcoalkyl or cycloalkyl
group unsubstituted or substituted with one, two or three suitable
substituents. In other embodiments, Ar.sub.3 is a 5-membered heteroaryl
group unsubstituted or substituted with one, two or three suitable
substituents. In still other embodiments, Ar.sub.3 is a 5- or 6-membered
aryl or heteroaryl group unsubstituted or substituted with one, two or
three suitable substituents.

[0060] Compositions and methods of Formula A-G are provided herein wherein
n.sub.3 is 0 or 1, and/or wherein n.sub.1 is 0, 1 or 2, and/or n.sub.2 is
0, 1 or 2. In some embodiments, R.sub.3a/R.sub.3g and R.sub.4a/R.sub.4g
are each hydrogen. In other embodiments, R.sub.3a/R.sub.3g and
R.sub.4a/R.sub.4g are not both substituted.

[0061] Compositions and methods of Formula A are provided herein wherein
Ar.sub.3 is a 5-membered heteroaryl group unsubstituted C.sub.1-C.sub.5
alkyl or unsubstituted C.sub.3-C.sub.5 cycloalkyl; and R.sub.2 is
hydrogen. In some embodiments, Ar.sub.1 is an unsubstituted or
substituted 6-membered aryl group or an unsubstituted or substituted
6-membered heteroaryl group. In other embodiments, W.sub.a is O.

[0063] Compositions and methods of Formulas A-G wherein W.sub.a is S, O,
or NH are described herein.

[0064] Compositions and methods of Formulas A-G are described herein
wherein Ar.sub.1 is an aryl or heteroaryl group unsubstituted or
substituted with one, two or three suitable substituents independently
selected from the group consisting of halogens; --CN; and --NO.sub.2; and
alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, --(CH.sub.2).sub.zCN where z is a whole
integer from 0 to 4, --OH, --C(O)H, --OC(O)H, --C(O)OH, --NH.sub.2,
--C(O)NH.sub.2, --NHC(O), --OC(O)NH.sub.2, --NHC(O)H, --NHC(O)OH groups
unsubstituted or substituted with one, two or three suitable substituents
independently selected from the group consisting of halogens,
unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl,
unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted
heterocycloalkyl, and unsubstituted heteroaryl.

[0065] Compositions and methods of Formulas A-G are described herein
wherein Ar.sub.2 is an aryl, heteroaryl, heterocylcoalkyl or cycloalkyl
group unsubstituted or substituted with one, two or three suitable
substituents independently selected from the group consisting of
halogens; --CN; and --NO.sub.2; and alkyl, alkenyl, heteroalkyl,
haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
--(CH.sub.2).sub.zCN where z is a whole integer from 0 to 4, --OH,
--C(O)H, --OC(O)H, --C(O)OH, --NH.sub.2, --C(O)NH.sub.2, --NHC(O),
--OC(O)NH.sub.2, --NHC(O)H, --NHC(O)OH groups unsubstituted or
substituted with one, two or three suitable substituents independently
selected from the group consisting of halogens, unsubstituted alkyl,
unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aryl,
unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and
unsubstituted heteroaryl. In some embodiments, Ar.sub.2 is an
unsubstituted or substituted pyridinyl. In other embodiments, Ar.sub.2 is
an unsubstituted or substituted quinazolinyl.

[0066] Compositions and methods of Formulas A-G are provided herein
wherein X.sub.b and Y.sub.b are each independently selected from O, N,
and NR.sub.c1 wherein R.sub.1 is unsubstituted alkyl or unsubstituted
aryl. In some emobiments, X.sub.b is N and Y.sub.b is NR.sub.c1. In other
embodiments, X.sub.b is O and Y.sub.b is N. In other embodiments, X.sub.b
is O and Y.sub.b is N, or X.sub.b is N and Y.sub.b is O.

[0070] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 10

[0071] wherein:

[0072] each Z is independently C, CR.sub.4, N, NR.sub.4, O, or S, provided
that no more than two Z's are heteroatoms and wherein no two adjacent Z's
are O or S, where R.sub.4 is H, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heteroaryl or substituted or
unsubstituted aryl;

[0073] each R.sub.1 is independently H, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, --OR.sub.c, --OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2,
--SR.sub.c, S(O).sub.jR.sub.c where j is 1 or 2, --NR.sub.c(O)R.sub.c,
--C(O)N(R.sub.c).sub.2, --C(O).sub.2R.sub.c, or --C(O)R.sub.c; or two
adjacent R.sub.1's are taken together to form a substituted or
unsubstituted aryl or heteroaryl; where each R.sub.c is independently H,
substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl; and

[0077] each R.sub.3 is independently H, substituted or unsubstituted
alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; and

[0080] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 12

[0081] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 13

[0082] wherein:

[0083] Z.sub.1 is CR.sub.4 or N; and

[0084] Z.sub.2 is O or S.

[0085] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 14

[0088] T is a mono-, bi-, or tricyclic, substituted or unsubstituted
cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0089] In some embodiments, T is 15

[0090] wherein A is a substituted or unsubstituted five or six-membered
aryl or heteroaryl; and B is a substituted or unsubstituted five or
six-membered arylene or heteroarylene, wherein A and B together form a
fused two-ring moiety.

[0091] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 16

[0092] In some embodiments, L is --C(O)NH--. In other embodiments, B is
substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene,
pyridazinylene, thiophenylene, imidazolylene, or pyrrolylene. In still
other embodiments, L is --NH--. In yet other embodiments, B is
substituted or unsubstituted phenylene, pyridinylene, pyrimidinylene,
pyridazinylene, thiophenylene, or imidazolylene.

[0093] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 17

[0094] wherein:

[0095] each of X.sub.1-X.sub.5 is independently C, CR, N, NR, S, or O,
wherein no more than three of X.sub.1-X.sub.5 is a heteroatom and no 2
adjacent ring atoms are O or S; and

[0096] each R is independently H, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --OR.sub.d,
--OC(O)R.sub.d, --NO.sub.2, --N(R.sub.d).sub.2, --SR.sub.d,
S(O).sub.jR.sub.d where j is 1 or 2, --NR.sub.dC(O)R.sub.d,
--C(O)N(R.sub.d).sub.2, --C(O).sub.2R.sub.d, or --C(O)R.sub.d; or two
adjacent R's, are taken together, to form a substituted or unsubstituted
aryl or heteroaryl; where each R.sub.d is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0097] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 18

[0098] In some embodiments, L is a covalent bond, --C(O)NH--,
--OCH.sub.2--, or --OCH.sub.2CH.sub.2--. In other embodiments, 19

[0099] is selected from the group consisting of: 20

[0100] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 21

[0101] wherein: 22

[0102] is selected from the group consisting of:

[0103] (a) L is selected from the group consisting of --O(substituted or
unsubstituted alkylene)-, and --C(O)(substituted or unsubstituted
alkenylene)-; and each of X.sub.1-X.sub.5 is independently CR, N--O, or
N, wherein no more than two of X.sub.1-X.sub.5 is N,

[0105] (b) L is --NH--; each of X.sub.1, X.sub.2, X.sub.4, and X.sub.5 is
independently CR or N; and X.sub.3 is independently CR.sub.6 or N,
wherein no more than two of X.sub.1-X.sub.5 is N,

[0106] where R.sub.6 is selected from the group consisting of H, halogen,
substituted or unsubstituted alkyl, substituted alkoxy, --C(O)R.sub.c,
--OC(O)R.sub.c, --NO.sub.2, --N(R.sub.c).sub.2, and --SR.sub.c;

[0107] each R.sub.c is independently H, substituted or unsubstituted
alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0108] (c) L is --NH--; each of X.sub.1, X.sub.3, and X.sub.5 is
independently CR or N; and each of X.sub.2 and X.sub.4 is independently
CR.sub.7 or N, wherein no more than two of X.sub.1-X.sub.5 is N;

[0110] each R.sub.c is independently H, substituted or unsubstituted
alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0111] (d) L is --C(O)NH--; each of X.sub.1, X.sub.2, X.sub.4, and X.sub.5
is independently CR or N; and X.sub.3 is independently CR.sub.8 or N,
wherein no more than two of X.sub.1-X.sub.5 is N, and when X.sub.3 is N,
at least one of X.sub.1, X.sub.2, X.sub.3, or X.sub.5 is not CH,

[0112] where R.sub.8 is selected from the group consisting of H, halogen,
substituted or unsubstituted alkyl, --OR.sub.c, substituted or
unsubstituted alkoxy, --C(O)R.sub.c, --OC(O)R.sub.c, --NO.sub.2,
--N(R.sub.c).sub.2, and --SR.sub.c;

[0113] each R.sub.c is independently H, substituted or unsubstituted
alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0114] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 23

[0115] In some embodiments, L is --NHC(O)--, --O(substituted or
unsubstituted alkylene)-, a covalent bond, -(substituted or unsubstituted
alkylene)-, --NHC(O)(substituted or unsubstituted alkylene)-,
--C(O)NH(substituted or unsubstituted alkylene)-, --NHC(O)(substituted or
unsubstituted alkenylene)-, or --C(O)NH(substituted or unsubstituted
alkenylene).

[0116] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 24

[0117] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 25

[0118] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 26

[0119] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 27

[0120] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 28

[0121] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 29

[0122] In some embodiments, L is a linker selected from the group
consisting of --NHC(O)--, --O(C.sub.1-C.sub.3 alkyl),
--NHC(O)CH.sub.2SCH.sub.2C(O)NH--, --CHCHCH.sub.2O--,
--CH.sub.2CH.sub.2--, --NHC(O)--(C.sub.1-C.sub.4 alkene),
--NHC(O)--(C.sub.1-C.sub.3 alkyl), and --CH.sub.2CH.sub.2C(O)NH--.

[0123] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 30

[0126] each of X.sub.1-X.sub.5 is independently C, CR, N--O, or N, wherein
no more than two of X.sub.1-X.sub.5 is N; where

[0127] each R is independently H, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, --OR.sub.d,
--OC(O)R.sub.d, --NO.sub.2, --N(R.sub.d).sub.2, --SR.sub.d,
S(O).sub.jR.sub.d where j is 1 or 2, --NR.sub.dC(O)R.sub.d,
--C(O)N(R.sub.d).sub.2, --C(O).sub.2R.sub.d, or --C(O)R.sub.d; or two
adjacent R's, are taken together, to form a substituted or unsubstituted
aryl or heteroaryl; where each R.sub.d is independently H, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0128] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 31

[0129] wherein: 32

[0130] is selected from the group consisting of:

[0131] (a) each of L and L.sub.1 is independently a linker selected from
the group consisting of a covalent bond, --O(substituted or unsubstituted
alkylene)-, --S--, -(substituted or unsubstituted alkylene)-, --C(O)--,
and --N(substituted or unsubstituted alkylene)-;

[0132] U is a substituted or unsubstituted cycloalkyl, aryl, or
heteroaryl; and

[0133] V is a substituted or unsubstituted cycloalkylene, heterocyclene,
arylene, or heteroarylene;

[0134] (b) L is a linker selected from the group consisting of a covalent
bond, --O(substituted or unsubstituted alkylene)-, --S--, -(substituted
or unsubstituted alkylene)-, --O--, --NH--, --C(O)--, --C(O)NH--, and
--N(substituted or unsubstituted alkylene)-;

[0135] L.sub.1 is a linker selected from the group consisting of a
covalent bond, --O(substituted or unsubstituted alkylene)-, --S--,
-(substituted or unsubstituted alkylene)-, --O--, --NH--, --C(O)--, and
--N(substituted or unsubstituted alkylene)-;

[0143] V is a substituted or unsubstituted cycloalkylene, heterocyclene,
arylene, or heteroarylene; and

[0144] (c) L is a linker selected from the group consisting of a covalent
bond, --O(substituted or unsubstituted alkylene)-, --S--, -(substituted
or unsubstituted alkylene)-, --O--, --NH--, --C(O)--, --C(O)NH--, and
--N(substituted or unsubstituted alkylene)-;

[0145] L.sub.1 is a linker selected from the group consisting of a
covalent bond, --O(substituted or unsubstituted C.sub.2-C.sub.5
alkylene)-, --S--, -(substituted or unsubstituted alkylene)-, --O--,
--NH--, --C(O)--, --C(O)NH--, and --N(substituted or unsubstituted
alkylene)-;

[0146] U is selected from the group consisting of substituted or
unsubstituted cycloalkyl; substituted aryl; and substituted or
unsubstituted heteroaryl; and

[0147] V is a substituted or unsubstituted cycloalkylene, heterocyclene,
arylene, or heteroarylene.

[0148] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 33

[0149] In some embodiments, L.sub.1 is a bond; and L is a bond or
--C(O)NH--. In other embodiments, U is substituted or unsubstituted
phenyl, thiazolyl, or pyridinyl; and V is substituted or unsubstituted
piperidinylene, thiazolylene, imidazolylene, or thiophenylene.

[0150] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 34

[0151] In some embodiments, L.sub.1 is a bond, --CH.sub.2O--,
--N(CH.sub.3)-- or --O--; and L is --CH.sub.2O-- or --NHC(O)--. In other
embodiments, U is substituted or unsubstituted phenyl, C.sub.3-C.sub.6
cycloalkyl, pyrimidine or pyridine.

[0152] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 35

[0153] In some embodiments, L.sub.1 is a --NH-- or --O--; and L is
--NHC(O)--. In other embodiments, U is substituted or unsubstituted
pyrmidyl.

[0154] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
kinase modulating compound according to the following formula are
provided herein: 36

[0166] each R.sub.3 is independently H, substituted or unsubstituted
alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; and

[0183] In some embodiments, the protein tyrosine kinase is selected from
the "HER" receptor tyrosine kinase subfamily, which includes EGFR
(epithelial growth factor receptor), HER2, HER3 and HER4. In further
embodiments, the protein tyrosine kinase is selected from the subfamily
consisting of insulin receptor (IR), insulin-like growth factor I
receptor (IGF-1R) and insulin receptor related receptor (IRR).

[0184] In some embodiments, the protein tyrosine kinase is selected from
the platelet derived growth factor receptor (PDGFR) subfamily, which
includes PDGFR .alpha., PDGFR .beta., CSFIR, c-kit and c-fms. In another
embodiment, the protein tyrosine kinase is the vascular endothelial
growth factor ("VEGF") receptor subgroup.

[0185] In some embodiments, the protein tyrosine kinase is selected from
the fetus liver kinase ("flk") receptor subfamily, which includes kinase
insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), flk-1R, flk-4
and fms-like tyrosine kinase 1 (flt-1). In further embodiments, the
protein tyrosine kinase is selected from the fibroblast growth factor
("FGF") receptor subgroup, which includes the receptors FGFR1, FGFR2,
FGFR3, and FGFR4, and the ligands, FGF1, FGF2, FGF3, FGF4, FGF5, FGF6,
and FGF7. In a still further embodiment, the protein tyrosine kinase is
the tyrosine kinase growth factor receptor family, c-Met.

[0189] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of an
fms-like tyrosine kinase 3 (FLT-3) receptor modulating compound are
provided herein. In one embodiment, the disease is cancer. In other
embodiments, the cancer is a malignant tumor, or a hematologic malignancy
such as leukemia and lymphoma. In some embodiments, the leukemia is acute
myelogenous leukemia (AML), a B-precursor cell acute lymphoblastic
leukemia, myelodysplastic leukemia, T-cell acute lymphoblastic leukemia
or chronic myelogenous leukemia (CML).

[0190] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a Stem
Cell Factor (SCF), c-kit, receptor modulating compound are provided
herein. In one embodiment, the disease is cancer. In other embodiments,
the cancer is a malignant tumor, or a hematologic malignancy such as
leukemia and lymphoma. In some embodiments, the cancer is small-cell lung
cancer, or breast cancer. In some embodiments, the leukemia is acute
myelogenous leukemia (AML). In some embodiments, the malignant tumor is a
germ cell tumor, a mast cell tumor, a gastrointestinal stromal tumor
(GIST), melanoma, or a neuroblastoma.

[0191] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
Bcr-Abl receptor modulating compound are provided herein. In one
embodiment, the disease is cancer. In other embodiments, the cancer is a
malignant tumor, or a hematologic malignancy such as leukemia and
lymphoma. In some embodiments, the leukemia is chronic myeloid leukemia
(CML) or acute myelogenous leukemia (AML).

[0192] Compositions and methods for treating a disease comprising
administering to a subject in need thereof an effective amount of a
Platelet-Derived Growth Factor (PDGF) receptor modulating compound are
provided herein. In one embodiment, the disease is cancer. In other
embodiments, the cancer is a malignant tumor, or a hematologic malignancy
such as leukemia and lymphoma. In some embodiments, the leukemia is acute
lymphoblastic leukemia (ALL). In some embodiments, the lymphoma is T-cell
lymphoma. In some embodiments, the malignant tumor is melanoma, or
glioblastoma. In a further embodiment, the disease is a nonmalignant
proliferation disease. In some embodiments, the nonmalignant
proliferation disease is atherosclerosis, or restenosis. In a still
further embodiment, the disease is a fibroproliferative disorder. In some
embodiments, the fibroproliferative disorder is obliterative
bronchiolitis.

[0193] These and other aspects of the present invention will become
evident upon reference to the following detailed description. In
addition, various references are set forth herein which describe in more
detail certain procedures or compositions, and are incorporated by
reference in their entirety.

DISCLOSURE OF THE INVENTION

[0194] To more readily facilitate an understanding of the invention and
its preferred embodiments, the meanings of terms used herein will become
apparent from the context of this specification in view of common usage
of various terms and the explicit definitions of other terms provided in
the glossary below or in the ensuing description.

[0195] Glossary of Terms

[0196] Unless otherwise stated, the following terms used in this
application, including the specification and claims, have the definitions
given below. It must be noted that, as used in the specification and the
appended claims, the singular forms "a," "an" and "the" include plural
referents unless the context clearly dictates otherwise. Definition of
standard chemistry terms may be found in reference works, including Carey
and Sundberg (1992) "ADVANCED ORGANIC CHEMISTRY 3.sup.RD ED." Vols. A and
B, Plenum Press, New York. Unless otherwise indicated, conventional
methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant DNA techniques and pharmacology, within the skill of the art
are employed.

[0197] The term "modulator" means a molecule that interacts with a target
either directly or indirectly. The interactions include, but are not
limited to, agonist, antagonist, and the like.

[0198] The term "agonist" means a molecule such as a compound, a drug, an
enzyme activator or a hormone that enhances the activity of another
molecule or the activity of a receptor site etiehr directly or
indirectly.

[0199] The term "antagonist" means a molecule such as a compound, a drug,
an enzyme inhibitor, or a hormone, that diminishes or prevents the action
of another molecule or the activity of a receptor site either directly or
indirectly.

[0200] The terms "effective amount" or "therapeutically effective amount"
refer to a sufficient amount of the agent to provide the desired
biological result. That result can be reduction and/or alleviation of the
signs, symptoms, or causes of a disease, or any other desired alteration
of a biological system. For example, an "effective amount" for
therapeutic use is the amount of the composition comprising a compound as
disclosed herein required to provide a clinically significant decrease in
a disease. An appropriate "effective" amount in any individual case may
be determined by one of ordinary skill in the art using routine
experimentation.

[0201] As used herein, the terms "treat" or "treatment" are synonymous
with the term "prevent" and are meant to indicate a postponement of
development of diseases, preventing the development of diseases, and/or
reducing severity of such symptoms that will or are expected to develop.
Thus, these terms include ameliorating existing disease symptoms,
preventing additional symptoms, ameliorating or preventing the underlying
metabolic causes of symptoms, inhibiting the disorder or disease, e.g.,
arresting the development of the disorder or disease, relieving the
disorder or disease, causing regression of the disorder or disease,
relieving a condition caused by the disease or disorder, or stopping the
symptoms of the disease or disorder.

[0202] By "pharmaceutically acceptable" or "pharmacologically acceptable"
is meant a material which is not biologically or otherwise undesirable,
i.e., the material may be administered to an individual without causing
any undesirable biological effects or interacting in a deleterious manner
with any of the components of the composition in which it is contained.

[0204] As used herein, the term "subject" encompasses mammals and
non-mammals. Examples of mammals include, but are not limited to, any
member of the Mammalian class: humans, non-human primates such as
chimpanzees, and other apes and monkey species; farm animals such as
cattle, horses, sheep, goats, swine; domestic animals such as rabbits,
dogs, and cats; laboratory animals including rodents, such as rats, mice
and guinea pigs, and the like. Examples of non-mammals include, but are
not limited to, birds, fish and the like. In one embodiment of the
present invention, the mammal is a human.

[0205] The term "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable and that possesses the desired
pharmacological activity of the parent compound. Such salts, for example,
include: (1) acid addition salts, formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,
glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,
malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic
acid, glucoheptonic acid, 4,4,-methylenebis-(3-hydroxy-2-ene-1-carboxylic
acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and
the like; (2) salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal ion, an
alkaline earth ion, or an aluminum ion; or coordinates with an organic
base. Acceptable organic bases include ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine, and the like.
Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide,
potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. It
should be understood that a reference to a pharmaceutically acceptable
salt includes the solvent addition forms or crystal forms thereof,
particularly solvates or polymorphs. Solvates contain either
stoichiometric or non-stoichiometric amounts of a solvent, and are often
formed during the process of crystallization. Hydrates are formed when
the solvent is water, or alcoholates are formed when the solvent is
alcohol. Polymorphs include the different crystal packing arrangements of
the same elemental composition of a compound. Polymorphs usually have
different X-ray diffraction patterns, infrared spectra, melting points,
density, hardness, crystal shape, optical and electrical properties,
stability, and solubility. Various factors such as the recrystallization
solvent, rate of crystallization, and storage temperature may cause a
single crystal form to dominate.

[0206] As used herein, the term "biological sample" is broadly defined to
include any cell, tissue, organ or multicellular organism. A biological
sample can be derived, for example, from cell or tissue cultures in
vitro. Alternatively, a biological sample can be derived from a living
organism or from a population of single cell organisms.

[0207] As used herein, the term "linker" means any divalent linking moiety
used to connect, join, or attach two chemical groups. For example,
linkers may be used to join two cyclic groups, such as to join two aryl
groups (e.g., phenyl), an aryl group to a cycloalkyl group, an aryl group
to a heterocyclyl group, a cycloalkyl group to a cycloalkyl group, a
cycloalkyl group to a heterocyclyl group, and the like. Representative
linkers include, but are not limited to, a covalent bond, -(substituted
or unsubstituted alkylene)-, -(substituted or unsubstituted alkenylene)-,
-(substituted or unsubstituted alkynylene)-, -(substituted or
unsubstituted cycloalkylene)-, -(substituted or unsubstituted
heterocyclylene)-, -(substituted or unsubstituted arylene)-, and
-(substituted or unsubstituted heteroarylene)-. Exemplary linkers also
include --O--, --S--, --S(O)--, --S(O).sub.2--, --S(O).sub.3--, --C(O)--,
--NH--, --N.dbd., --N.dbd.N--, .dbd.N--N.dbd., --C(O)NH--, --S(O)NH--,
and the like. Additional examples of linkers include --O(substituted or
unsubstituted alkylene)-, --N(substituted or unsubstituted alkylene)-,
--NHC(O)(substituted or unsubstituted alkylene)-, --C(O)(substituted or
unsubstituted alkenylene)-, --NHC(O)(substituted or unsubstituted
alkylene)S(substituted or unsubstituted alkylene)C(O)NH--,
--NHC(O)(substituted or unsubstituted alkenylene)-, and the like.
Linkers, as represented herein, embrace divalent moieties in any
chemically feasible directionality. For example, compounds comprising a
linker-C(O)NH-- which attaches two aryl groups, Ar.sub.1 to Ar.sub.2,
include Ar.sub.1--C(O)NH--Ar.sub.2 as well as Ar.sub.1--NHC(O)--Ar.sub.2.

[0208] As used herein, the term "halogen" includes fluorine, chlorine,
bromine, and iodine.

[0210] As used herein, "lower alkyl" means an alkyl having from 1 to 5
carbon atoms.

[0211] As used herein, an "alkenyl group" includes a monovalent unbranched
or branched hydrocarbon chain having one or more double bonds therein.
The double bond of an alkenyl group can be unconjugated or conjugated to
another unsaturated group. Suitable alkenyl groups include, but are not
limited to, (C.sub.2-C.sub.8) alkenyl groups, such as vinyl, allyl,
butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl,
2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. An
alkenyl group can be unsubstituted or substituted.

[0212] As used herein, "alkynyl group" includes a monovalent unbranched or
branched hydrocarbon chain having one or more triple bonds therein. The
triple bond of an alkynyl group can be unconjugated or conjugated to
another unsaturated group. Suitable alkynyl groups include, but are not
limited to, (C.sub.2-C.sub.6) alkynyl groups, such as ethynyl, propynyl,
butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl,
4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. An alkynyl group can be
unsubstituted or substituted.

[0213] The terms "trifluoromethyl," "sulfonyl," and "carboxyl" include
CF.sub.3, SO.sub.3H, and CO.sub.2H, respectively.

[0214] The term "alkoxy" as used herein includes --O-(alkyl), wherein
alkyl is defined above.

[0215] As used herein, "alkoxyalkoxy" includes --O-(alkyl)-O-(alkyl),
wherein each "alkyl" is independently an alkyl group defined above.

[0217] As used herein, "alkoxycarbonylalkyl" includes
-(alkyl)-C(O)O-(alkyl), wherein alkyl is defined above.

[0218] As used herein, "alkoxyalkyl" means -(alkyl)-O-(alkyl), wherein
each "alkyl" is independently an alkyl group defined above.

[0219] As used herein, the term "aryl" (Ar) refers to a monocyclic, or
fused or spiro polycyclic, aromatic carbocycle (ring structure having
ring atoms that are all carbon) having from 3 to 12 ring atoms per ring.
Illustrative examples of aryl groups include the following moieties: 52

[0220] and the like.

[0221] As used herein, the term "heteroaryl" (heteroAr) refers to a
monocyclic, or fused or spiro polycyclic, aromatic heterocycle (ring
structure having ring atoms selected from carbon atoms as well as
nitrogen, oxygen, and sulfur heteroatoms) having from 3 to 12 ring atoms
per ring. Illustrative examples of aryl groups include the following
moieties: 53

[0222] As used herein, the term "cycloalkyl" refers to a saturated or
partially saturated, monocyclic or fused or spiro polycyclic, carbocycle
having from 3 to 12 ring atoms per ring. Illustrative examples of
cycloalkyl groups include the following moieties: 54

[0223] and the like.

[0224] As used herein, the term "heterocycloalkyl" refers to a monocyclic,
or fused or spiro polycyclic, ring structure that is saturated or
partially saturated and has from 3 to 12 ring atoms per ring selected
from C atoms and N, O, and S heteroatoms. Illustrative examples of
heterocycloalkyl groups include: 55

[0225] As used herein, "aryloxy" includes --O-aryl group, wherein aryl is
as defined above. An aryloxy group can be unsubstituted or substituted.

[0226] As used herein, "arylalkyl" includes -(alkyl)-(aryl), wherein alkyl
and aryl are defined above.

[0227] As used herein, "arylalkyloxy" includes --O-(alkyl)-(aryl), wherein
alkyl and aryl are defined above.

[0228] As used herein, "cycloalkyl" includes a monocyclic or polycyclic
saturated ring comprising carbon and hydrogen atoms and having no
carbon-carbon multiple bonds. Examples of cycloalkyl groups include, but
are not limited to, (C.sub.3-C.sub.7)cycloalkyl groups, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and
saturated cyclic and bicyclic terpenes. A cycloalkyl group can be
unsubstituted or substituted. Preferably, the cycloalkyl group is a
monocyclic ring or bicyclic ring.

[0229] As used herein, "cycloalkyloxy" includes --O-(cycloalkyl), wherein
cycloalkyl is defined above.

[0230] As used herein, "cycloalkylalkyloxy" includes
--O-(alkyl)-(cycloalkyl), wherein cycloalkyl and alkyl are defined above.

[0231] As used herein, the term "alkylidene" includes the divalent radical
--C.sub.nH.sub.2n--, wherein n is an integer from 1 to 8, such as
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2C-
H.sub.2--, and the like, unsubstituted or substituted with one or more
alkyl groups.

[0232] As used herein, "heteroatom-containing alkylidene" includes an
alkylidene wherein at least one carbon atom is replaced by a heteroatom
selected from nitrogen, oxygen, or sulfur, such as
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, and the like, unsubstituted or
substituted with one or more alkyl groups.

[0233] As used herein, "aminoalkoxy" includes --O-(alkyl)-NH.sub.2,
wherein alkyl is defined above.

[0234] As used herein, "mono-alkylamino" includes --NH(alkyl), wherein
alkyl is defined above.

[0235] As used herein, "di-alkylamino" includes --N(alkyl)(alkyl), wherein
each "alkyl" is independently an alkyl group defined above.

[0236] As used herein, "mono-alkylaminoalkoxy" includes
--O-(alkyl)-NH(alkyl), wherein each "alkyl" is independently an alkyl
group defined above.

[0237] As used herein, "di-alkylaminoalkoxy" includes
--O-(alkyl)N(alkyl)(alkyl), wherein each "alkyl" is independently an
alkyl group defined above.

[0238] As used herein, "arylamino" includes --NH(aryl), wherein aryl is
defined above.

[0239] As used herein, "arylalkylamino" includes --NH-(alkyl)-(aryl),
wherein alkyl and aryl are defined above.

[0240] As used herein, "alkylamino" includes --NH(alkyl), wherein alkyl is
defined above.

[0241] As used herein, "cycloalkylamino" includes --NH-(cycloalkyl),
wherein cyclohexyl is defined above.

[0242] As used herein, "cycloalkylalkylamino" includes
--NH-(alkyl)-(cycloalkyl), wherein alkyl and cycloalkyl are defined
above.

[0243] As used herein, "aminoalkyl" includes -(alkyl)-NH.sub.2, wherein
alkyl is defined above.

[0244] As used herein, "mono-alkylaminoalkyl" includes -(alkyl)-NH(alkyl),
wherein each "alkyl" is independently an alkyl group defined above.

[0245] As used herein, "di-alkylaminoalkyl" includes
-(alkyl)-N(alkyl)(alkyl), wherein each "alkyl" is independently an alkyl
group defined above.

[0246] The term "whole integer" is intended to include whole numbers. For
example, a whole integer from 0 to 4 would include 0, 1, 2, 3, and 4.

[0247] Sulfonyl refers to the presence of a sulfur atom, which is
optionally linked to another moiety such as an aliphatic group, an
aromatic group, an aryl group, an alicyclic group, or a heterocyclic
group. Aryl or alkyl sulfonyl moieties have the formula
--SO.sub.2R.sub.d, and alkoxy moieties have the formula --O--R.sub.d,
wherein R.sub.d is alkyl, as defined above, or is aryl wherein aryl is
phenyl; optionally substituted with 1-3 substituents independently
selected from halo (fluoro, chloro, bromo or iodo), lower alkyl
(C.sub.1-6) and lower alkoxy (C.sub.1-6).

[0248] As used herein, the term "substituted" means that the specified
group or moiety bears one or more suitable substituents.

[0249] As used herein, the term "unsubstituted" means that the specified
group bears no substituents.

[0250] As used herein, the term "optionally substituted" means that the
specified group is unsubstituted or substituted by one or more
substituents.

[0251] Molecular embodiments of the present invention may possess one or
more chiral centers and each center may exist in the R or S
configuration. The present invention includes all diastereomeric,
enantiomeric, and epimeric forms as well as the appropriate mixtures
thereof. Stereoisomers may be obtained, if desired, by methods known in
the art as, for example, the separation of stereoisomers by chiral
chromatographic columns. Additionally, the compounds of the present
invention may exist as geometric isomers. The present invention includes
all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well
as the appropriate mixtures thereof.

[0252] Certain functional groups contained within the compounds of the
present invention can be substituted for bioisosteric groups, that is,
groups which have similar spatial or electronic requirements to the
parent group, but exhibit differing or improved physicochemical or other
properties. Suitable examples are well known to those of skill in the
art, and include, but are not limited to moieties described in Patini et
al., Chem, Rev, 1996, 96, 3147-3176 and references cited therein.

[0253] In addition, the compounds of the present invention can exist in
unsolvated as well as solvated forms with pharmaceutically acceptable
solvents such as water, ethanol, and the like. In general, the solvated
forms are considered equivalent to the unsolvated forms for the purposes
of the present invention.

[0254] To more readily facilitate an understanding of the invention and
its preferred embodiments, the meanings of terms used herein will become
apparent from the context of this specification in view of common usage
of various terms and the explicit definitions of other terms provided in
the glossary below or in the ensuing description.

[0255] Compounds

[0256] In one aspect, the present invention is directed to compounds,
compositions, and methods for treating conditions associated with
abnormal kinase activity. In one embodiment, compounds useful in the
invention are derivatives of isoxazoles, pyrazoles and isothiazoles. When
the compounds of the invention contain one or more chiral centers, the
invention includes optically pure forms as well as mixtures of
stereoisomers or enantiomers.

[0257] Thus, the invention provides methods for modulating various kinases
by providing an effective amount of a compound of the formulas described
herein.

[0258] Salts of the compounds may be used for therapeutic and prophylactic
purposes, where the salt is preferably a pharmaceutically acceptable
salt. Examples of pharmaceutically acceptable salts include those derived
from mineral acids, such as hydrochloric, hydrobromic, phosphoric,
metaphosphoric, nitric and sulphuric acids, and organic acids, such as
tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric,
benzoic, glycolic, gluconic, succinic and methanesulphonic and
arylsulphonic, for example Q-toluenesulphonic, acids.

[0259] A "prodrug" refers to a drug or compound in which the
pharmacological action results from conversion by metabolic processes
within the body. Prodrugs are generally drug precursors that, following
administration to a subject and subsequent absorption, are converted to
an active, or a more active species via some process, such as conversion
by a metabolic pathway. Some prodrugs have a chemical group present on
the prodrug that renders it less active and/or confers solubility or some
other property to the drug. Once the chemical group has been cleaved
and/or modified from the prodrug the active drug is generated. Prodrugs
may be designed as reversible drug derivatives, for use as modifiers to
enhance drug transport to site-specific tissues. Additionally, prodrugs
can increase the effective water solubility of the therapeutic compound
for targeting to regions where water is the principal solvent. See, e.g.,
Fedorak et al., Am. J. Physiol., 269: G210-218 (1995); McLoed et al.,
Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom.,
6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37,
87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988);
Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V.
Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug
Design, American Pharmaceutical Association and Pergamon Press, 1987.
Prodrug forms of the above described compounds, wherein the prodrug is
metabolized in vivo to produce a derivative as set forth above are
included within the scope of the claims. Indeed, some of the
above-described derivatives may be a prodrug for another derivative or
active compound. The invention further provides for the optical isomers
of the compounds disclosed herein, especially those resulting from the
chiral carbon atoms in the molecule. In additional embodiments of the
invention, mixtures of enantiomers and/or diastereoisomers, resulting
from a single preparative step, combination, or interconversion may also
be useful for the applications described herein.

[0260] In another aspect, compositions containing the above described
analogs and derivatives are provided. Preferably, the compositions are
formulated to be suitable for pharmaceutical or clinical use by the
inclusion of appropriate carriers or excipients.

[0261] Groups such as carbonyl, carboxyl, alkoxy, amino, and cyano groups,
etc., as shown in the formula above, need not be directly bound to the
para position; they may be included elsewhere in the alkyl, alkenyl or
alkynyl substituent. Thus, also acceptable substituents are the following
representative forms:

[0263] --CH.sub.2CH.sub.2CH.sub.2SH; --CH.sub.2OC(O)CH.sub.3;
--CH.sub.2NHC(O)CH.sub.2C(O)CH.sub.3; --NHC(O)CH.sub.2CH.sub.2CH.sub.3
each of which may further be substituted with a cycloalkyl,
heterocycloalkyl, aryl or heteroaryl group.

[0264] It will also be evident that these substituents include, for
example, trifluoromethyl, difluoromethyl and fluoromethyl (alkyl
substituted by halo) and trifluoromethoxy, difluoromethoxy and
fluoromethoxy (alkyl where one carbon is replaced by O and is further
substituted by halo).

[0265] Compounds of the invention which contain carboxyl groups or which
contain amino groups may be supplied in the forms of their
pharmaceutically acceptable salts. Pharmaceutically acceptable salts of
carboxylic acids include inorganic salts such as salts of sodium,
potassium, calcium, magnesium and the like or salts formed with organic
bases such as caffeine. Salts of amines are acid addition salts formed
from inorganic acids such as hydrochloric, sulfuric, phosphoric acids or
may be salts of organic acids such as acetates, maleates, propionates,
and the like.

[0266] The invention also provides prodrug forms of the compounds
described herein, wherein the prodrug is metabolized in vivo to produce a
derivative as set forth above. Indeed, some of the above described
derivatives may be a prodrug for another derivative or active compound.
The invention further provides for the optical isomers of the compounds
disclosed herein, especially those resulting from the chiral carbon atoms
in the molecule. In additional embodiments of the invention, mixtures of
enantiomers and/or diastereoisomers, resulting from a single preparative
step, combination, or interconversion are provided.

[0267] In another aspect of the invention, compositions containing the
above described analogs and derivatives are provided. Preferably, the
compositions are formulated to be suitable for pharmaceutical or clinical
use by the inclusion of appropriate carriers or excipients.

[0268] In yet another aspect of the invention, pharmaceutical formulations
are provided comprising at least one compound described above, or a
pharmaceutically acceptable salt or solvate thereof, together with one or
more pharmaceutically acceptable carriers, diluents or excipients.

[0269] The compounds of the invention, especially when used in the
invention methods and compositions, may be "conjugated"--that is they may
be coupled to additional moieties that do not destroy their ability to
modulate kinases. For example, the compounds might be coupled to a label
such as a radioactive label, a fluorescent label and the like, or may be
coupled to targeting agents such as antibodies or fragments, or to
fragments to aid purification such as FLAG or a histidine tag. The
compounds may also be coupled to specific binding partners such as biotin
for use in assay procedures or to moieties that alter their biological
half-lives such as polyethylene glycol. Thus, the methods of the
invention employ the invention compounds per se as well as conjugates
thereof.

[0270] Synthesis of Compounds

[0271] Compounds of the present invention may be synthesized using
standard synthetic techniques known to those of skill in the art or using
methods known in the art in combination with methods described herein.
See, e.g., March, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., (Wiley 1992);
Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 3.sup.rd Ed., Vols. A and
B (Plenum 1992), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC
SYNTHESIS 2.sup.nd Ed. (Wiley 1991). General methods for the preparation
of compound as disclosed herein may be derived from known reactions in
the field, and the reactions may be modified by the use of appropriate
reagents and conditions, as would be recognized by the skilled person,
for the introduction of the various moieties found in the formulae as
provided herein.

[0272] The compounds of the invention are synthesized by methods well
known in the art. The compounds of the invention are ureas or cyclic
forms thereof and can be synthesized using generally known procedures for
urea synthesis.

[0273] In one group of methods, an amine is reacted with an isocyanate in
an aprotic solvent. Typically, in some embodiments, a molar excess of the
amine is used in the presence of an aprotic solvent and the reaction is
conducted at room temperature. The reaction mixture is then poured into
water and precipitated with salt to recover the crude product which is
then purified according to standard methods.

[0274] In alternative methods, the ureas are formed from two separate
amine reactants in the presence of a condensing agent such as
1,1,carbonyldiimidazole (CDI) in the presence of an inert nonpolar
solvent such as dichloromethane. One of the amines is first added to a
solution of CDI in solvent under cooling conditions and then stirred at
room temperature with the other amine. After removal of solvent, the
crude product can be purified using standard procedures.

[0275] In still another method, one of the amines is added in an aprotic
solvent to a solution of triphosgene and then treated with the other
amine reactant dissolved in an inert solvent in the presence of base such
as triethylamine. After reaction at room temperature, the mixture may be
diluted with, for example, ethylacetate and washed with water and brine,
dried and purified.

[0276] In still another method, one of the amine components is treated
with 4-nitrophenylchloroformate in the presence of mild base in a solvent
such as N-methylpyrrolidone (NMP). The other amine is then added and the
reaction mixture heated, then cooled, poured into water, extracted into
chloroform and further purified.

[0277] Alternatively, the urea may be formed by the reaction of an amine
with the counterpart halo acylamine which is formed from the parent amine
by treatment with phosgene and base in an inert solvent such as methylene
dichloride or by reacting an amine with its counterpart amine with an
acyl amine containing an alternate leaving group formed by reaction of
that amine with 4-nitrophenylchloroformate in the presence of an amine
base and in an inert solvent.

[0279] Cyclized forms of the ureas may be obtained by treating the formed
urea with dibromo derivatives of the bridge, typically in the presence of
a strong base and in an inert aprotic polar solvent.

[0280] The ureas may be converted to thioureas by treating with Lawesson's
reagent in the presence of toluene.

[0281] For compounds having the moiety Ar.sup.1-L-Ar.sup.2 is obtained by
first protecting the amino group of p-hydroxy aniline destined to become
Ar.sup.1 with a protecting agent such as Boc and then coupling the
hydroxy group of Ar.sup.1 to an aryl alkyl halide. This coupling is
conducted in the presence of strong base and in an aprotic solvent. After
deprotection, the urea is formed by reaction with the isoxazole
isocyanate. These techniques are exemplified below.

[0282] Selected examples of covalent linkages and precursor functional
groups which yield them are given in the Table entitled "Examples of
Covalent Linkages and Precursors Thereof." Precursor functional groups
are shown as electrophilic groups and nucleophilic groups. The functional
group on the organic substance may be attached directly, or attached via
any useful spacer or linker as defined below.

[0283] In general, carbon electrophiles are susceptible to attack by
complementary nucleophiles, including carbon nucleophiles, wherein an
attacking nucleophile brings an electron pair to the carbon electrophile
in order to form a new bond between the nucleophile and the carbon
electrophile.

[0284] Suitable carbon nucleophiles include, but are not limited to alkyl,
alkenyl, aryl and alkynyl Grignard, organolithium, organozinc, alkyl-,
alkenyl, aryl- and alkynyl-tin reagents (organostannanes), alkyl-,
alkenyl-, aryl- and alkynyl-borane reagents (organoboranes and
organoboronates); these carbon nucleophiles have the advantage of being
kinetically stable in water or polar organic solvents. Other carbon
nucleophiles include phosphorus ylids, enol and enolate reagents; these
carbon nucleophiles have the advantage of being relatively easy to
generate from precursors well known to those skilled in the art of
synthetic organic chemistry. Carbon nucleophiles, when used in
conjunction with carbon electrophiles, engender new carbon-carbon bonds
between the carbon nucleophile and carbon electrophile.

[0285] Non-carbon nucleophiles suitable for coupling to carbon
electrophiles include but are not limited to primary and secondary
amines, thiols, thiolates, and thioethers, alcohols, alkoxides, azides,
semicarbazides, and the like. These non-carbon nucleophiles, when used in
conjunction with carbon electrophiles, typically generate heteroatom
linkages (C--X--C), wherein X is a hetereoatom, e.g, oxygen or nitrogen.

[0286] The term "protecting group" refers to chemical moieties that block
some or all reactive moieties and prevent such groups from participating
in chemical reactions until the protective group is removed. It is
preferred that each protective group be removable by a different means.
Protective groups that are cleaved under totally disparate reaction
conditions fulfill the requirement of differential removal. Protective
groups can be removed by acid, base, and hydrogenolysis. Groups such as
trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile
and may be used to protect carboxy and hydroxy reactive moieties in the
presence of amino groups protected with Cbz groups, which are removable
by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic
acid and hydroxy reactive moieties may be blocked with base labile groups
such as, without limitation, methyl, ethyl, and acetyl in the presence of
amines blocked with acid labile groups such as t-butyl carbamate or with
carbamates that are both acid and base stable but hydrolytically
removable.

[0287] Carboxylic acid and hydroxy reactive moieties may also be blocked
with hydrolytically removable protective groups such as the benzyl group,
while amine groups capable of hydrogen bonding with acids may be blocked
with base labile groups such as Fmoc. Carboxylic acid reactive moieties
may be protected by conversion to simple ester derivatives as exemplified
herein, or they may be blocked with oxidatively-removable protective
groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be
blocked with fluoride labile silyl carbamates.

[0288] Allyl blocking groups are useful in then presence of acid- and
base-protecting groups since the former are stable and can be
subsequently removed by metal or pi-acid catalysts. For example, an
allyl-blocked carboxylic acid can be deprotected with a
Pd.sub.0-catalyzed reaction in the presence of acid labile t-butyl
carbamate or base-labile acetate amine protecting groups. Yet another
form of protecting group is a resin to which a compound or intermediate
may be attached. As long as the residue is attached to the resin, that
functional group is blocked and cannot react. Once released from the
resin, the functional group is available to react.

[0289] Typically blocking/protecting groups may be selected from: 57

[0290] Other protecting groups are described in Greene and Wuts,
Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New
York, N.Y., 1999, which is incorporated herein by reference in its
entirety.

[0291] Biological Activity

[0292] Protein kinases (PKs) play a role in signal transduction pathways
regulating a number of cellular functions, such as cell growth,
differentiation, and cell death. PKs are enzymes that catalyze the
phosphorylation of hydroxy groups on tyrosine, serine and threonine
residues of proteins. Abnormal PK activity has been related to disorders
ranging from relatively non life threatening diseases such as psoriasis
to extremely virulent diseases such as glioblastoma (brain cancer). In
addition, a variety of tumor types have dysfunctional growth factor
receptor tyrosine kinases, resulting in inappropriate mitogenic
signaling. Protein kinases are believed to be involved in many different
cellular signal transduction pathways. In particular, protein tyrosine
kinases (PTK) are attractive targets in the search for therapeutic
agents, not only for cancer, but also against many other diseases.
Blocking or regulating the kinase phosphorylation process in a signaling
cascade may help treat conditions such as cancer or inflammatory
processes.

[0293] Protein tyrosine kinases are a family of tightly regulated enzymes,
and the aberrant activation of various members of the family is one of
the hallmarks of cancer. The protein-tyrosine kinase family includes
Bcr-Abl tyrosine kinase, and can be divided into subgroups that have
similar structural organization and sequence similarity within the kinase
domain. The members of the type III group of receptor tyrosine kinases
include the platelet-derived growth factor (PDGF) receptors (PDGF
receptors .alpha. and .beta.), colony-stimulating factor (CSF-1) receptor
(CSF-1R, c-Fms), FLT-3, and stem cell or steel factor receptor (c-kit).

[0295] Inhibition by the compounds provided herein can be determined using
any suitable assay. In one embodiment, inhibition is determined in vitro.
In a specific embodiment, inhibition is assessed by phosphorylation
assays. Any suitable phosphorylation assay can be employed. For example,
membrane autophosphorylation assays, receptor autophosphorylation assays
in intact cells, and ELISA's can be employed. See, e.g., Gazit, et al.,
J. Med. Chem. (1996) 39: 2170-2177, Chapter 18 in CURRENT PROTOCOLS IN
MOLECULAR BIOLOGY (Ausubel, et al., eds. 2001). Cells useful in such
assays include cells with wildtype or mutated forms. In one embodiment,
the wildtype is a kinase that is not constitutively active, but is
activated with upon dimerization. For example, the mutant FLT3 kinase is
constitutively active via internal tandem duplication mutations or point
mutations in the activation domain. Suitable cells include those derived
through cell culture from patient samples as well as cells derived using
routine molecular biology techniques, e.g., retroviral transduction,
transfection, mutagenesis, etc. Exemplary cells include Ba/F3 or 32Dc13
cells transduced with, e.g., MSCV retroviral constructs FLT3-ITD (Kelly
et al., 2002); Molm-13 and Molm14 cell line (Fujisaki Cell Center,
Okayama, Japan); HL60 (AML-M3), AML193 (AML-M5), KG-1, KG-la, CRL-1873,
CRL-9591, and THP-1 (American Tissue Culture Collection, Bethesda, Md.);
or any suitable cell line derived from a patient with a hematopoietic
malignancy.

[0296] In some embodiments, the compounds described herein significantly
inhibit receptor tyrosine kinases. A significant inhibition of a receptor
tyrosine kinase activity refers to an IC.sub.50 of less than or equal to
100 .mu.M. Preferably, the compound can inhibit activity with an
IC.sub.50 of less than or equal to 50 .mu.M, more preferably less than or
equal to 10 .mu.M, more preferably less than 1 .mu.M, or less than 100
nM, most preferably less than 50 nM. Lower IC.sub.50's are preferred
because the IC.sub.50 provides an indication as to the in vivo
effectiveness of the compound. Other factors known in the art, such as
compound half-life, biodistribution, and toxicity should also be
considered for therapeutic uses. Such factors may enable a compound with
a lower IC.sub.50 to have greater in vivo efficacy than a compound having
a higher IC.sub.50. Preferably, a compound that inhibits activity is
administered at a dose where the effective tyrosine phosphorylation,
i.e., IC.sub.50, is less than its cytotoxic effects, LD.sub.50.

[0297] In some embodiments, the compounds selectively inhibit one or more
kinases. Selective inhibition of a kinase, such as FLT3, p38 kinase,
STK10, MKNK2, Bcr-Abl, c-kit, or PDGFR, is achieved by inhibiting
activity of one kinase, while having an insignificant effect on other
members of the superfamily.

[0298] c-kit

[0299] The Stem Cell Factor (SCF) receptor c-kit is a receptor protein
tyrosine kinase that initiates cell growth and proliferation signal
transduction cascades in response to SCF binding. c-kit is a 145-kD
transmembrane glycoprotein and is the normal cellular homolog of the
v-kit retroviral oncogene, It is also a member of the Type III
transmembrane receptor protein tyrosine kinase subfamily, which includes
the macrophage colony-stimulating factor-1 receptor, also known as the
FMS receptor, the related FLT-3 receptor, and the platelet-derived growth
factor (PDGF) .alpha. and .beta. receptors. The c-kit gene product is
expressed in hematopoietic progenitor cells, mast cells, germ cells,
interstitial cells of Cajal (ICC), and some human tumors. Inactivating
mutations of c-kit or its ligand, Steel factor (SLF), have demonstrated
that the normal functional activity of the c-kit gene product is
essential for maintenance of normal hematopoeisis, melanogenesis,
genetogensis, and growth and differentiation of mast cells and ICC. SLF
is produce by human and murine hematopoietic stromal cells, including
endothelial cells, fibroblasts, and bone marrow-derived stromal cells.

[0300] In addition to its importance in normal cellular physiologic
activities, c-kit plays a role in the biological aspects of certain human
cancers, including germ cell tumors, mast cell tumors, gastrointestinal
stromal tumors (GIST), small-cell lung cancer, melanoma, breast cancer,
acute myelogenous leukemia (AML), and neuroblastoma. Proliferation of
tumor cell growth mediated by c-kit can occur by a specific mutation of
the c-kit polypeptide that results in ligand independent activation or by
autocrine stimulation of the receptor. In the former case, mutations that
cause constitutive activation of c-kit kinase activity in the absence of
SCF binding are implicated in malignant human cancers, including
gastrointestinal stromal tumors, germ cell tumors, mast cell tumors, and
myeloid leukemia's and in mastocytosis.

[0301] The activity of the c-kit receptor protein tyrosine kinase is
regulated in normal cells, and as discussed the deregulated c-kit kinase
activity is implicated in the pathogenesis of human cancers. In some
types of tumors, inhibition of c-kit activity reduces cellular
proliferation, suggesting a role for use of pharmacologic inhibitors of
c-kit in the treatment of c-kit dependent malignancies.

[0302] In one embodiment, compositions and methods provided herein are
effective to modulate the activity of c-kit. In other embodiments,
compositions and methods provided herein are effective to selectively
modulate the activity of c-kit.

[0305] The Bcr domain interferes with the intramolecular Abl inhibitory
loop and unveils a constitutive kinase activity that is absent in the
normal Abl protein. Bcr-Abl tyrosine kinase is a potent inhibitor of
apoptosis, and it is well accepted that the oncoprotein expresses a
constitutive tyrosine kinase activity that is necessary for its cellular
transforming activity. Constitutive activity of the fusion tyrosine
kinase Bcr-Abl has been established as the characteristic molecular
abnormality present in virtually all cases of chronic myeloid leukemia
(CML) and up to 20 percent of adult acute lymphoblastic leukemia (ALL)
[Faderl S. et al., N Engl J Med 341, 164-172 (1999); Sawyers C. L., N
Engl J Med 340, 1330-1340 (1999)].

[0306] Mutations present in the kinase domain of the Bcr-Abl gene of
patients suffering from CML or Ph+ ALL account for the biological
resistance of these patients towards STI571 treatment in that said
mutations lead to resistance of the Bcr-Abl tyrosine kinase towards
inhibition by STI571. Novel therapies for CML need to address this
emerging problem of clinical resistance to STI571 (Gleevec). Because
tumor progression in patients receiving STI571 seem to be mediated by
amplification of or mutation in the Bcr-Abl gene that causes the tyrosine
kinase to be less efficiently inhibited by the drug, newer tyrosine
kinase inhibitors may be susceptible to the same mechanisms of
resistance. None the less, these findings are extremely valuable in the
development of new compounds or combinations of compounds which are
capable to overcome resistance towards treatment with STI571.
Furthermore, in view of the large number of protein kinase inhibitors and
the multitude of proliferative and other PK-related diseases, there is an
ever-existing need to provide novel classes of compounds that are useful
as PK inhibitors and thus in the treatment of these PTK related diseases.

[0307] In one embodiment, compositions and methods provided herein are
effective to modulate the activity of Bcr-Abl. In other embodiments,
compositions and methods provided herein are effective to selectively
modulate the activity of Bcr-Abl. In a further embodiment, compositions
of Formula G, e.g., compounds described in Examples M and O, inhibit the
protein tyrosine kinase associated with mutated bcr-abl, which gives rise
to observed clinical resistance towards treatment with STI571.

[0308] PDGFR

[0309] Platelet-Derived Growth factor Receptors (PDGFR's) are receptor
tyrosine kinases that regulate proliferative and chemotatic responses.
PDGFR's have two forms--PDGFR-.alpha. (CD140a) and PDGFR-.beta. (CD140b).
PDGFRs are normally found in connective tissue and glia but are lacking
in most epithelia, and PDGF expression has been shown in a number of
different solid tumors, from glioblastomas to prostate carcinomas. For
instance, PDGFR kinases are involved in various cancers such as T-cell
lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia
(AML), melanoma, glioblastoma and others (see Bellamy W. T. et al.,
Cancer Res. 1999, 59, 728-733). In these various tumor types, the
biological role of PDGF signaling can vary from autocrine stimulation of
cancer cell growth to more subtle paracrine interactions involving
adjacent stroma and angiogenesis. Furthermore, PDGF has been implicated
in the pathogenesis of several nonmalignant proliferation diseases,
including atherosclerosis, restenosis following vascular angioplasty and
fibroproliferative disorders such as obliterative bronchiolitis.
Therefore, inhibiting the PDGFR kinase activity with small molecules may
interfere with tumor growth and angiogenesis.

[0310] The binding of PDGFR to its receptor activates the intracellular
tyrosine kinase, resulting in the autophorylation of the receptor as well
as other intracellular substrates such as Src, GTPase Activating Protein
(GAP), and phosphatidylinositol-3-phosphate. Upon autophorylation the
PDGFR also forms complexes with other signaling moieties including
phospholipase C-.gamma. (PLC-.gamma.), phosphatidylinositol-3-kinase
(PI3K), and raf-1. It appears to be involved in communication between
endothelial cells and pericytes, a communication that is essential for
normal blood vessel development.

[0311] It has been found previously that the disruption of the
PDGFR-.beta. in mice oblates neovascular pericytes that from part of the
capillary wall. See Lindahl, P., et al., Science (1997) 227:242-245;
Hellstrom, M., et al., Development (1999) 126:3047-3055. A recent study
by Bergers, G., et al., J. Clin. Invest. (2003) 111:1287-1295 has
suggested that inhibition of PDGFR kinase activity by certain compounds
such as SU6668 or ST1571/Gleevec inhibits tumor growth and that these
compounds combined with VEGFR inhibitor SU5416 were very effective in
reducing tumor growth. Further, inhibition of PDGFR-.beta. by Gleevec
enhanced tumor chemotherapeutic efficacy in mice. Pietras, K., et al.,
Cancer Res. (2002) 62:5476-5484. A review of PDGFR receptors as cancer
drug targets by Pietras, K., et al., appears in Cancer Cell. (2003)
3:439-443. Inhibition of this kinase activity is also effective where
abnormal forms of PDGFR, such as the TEL/PDGFR-.beta. fusion protein
associated with chronic myelomonocytic leukemia (CMML) is produced. See
also, Grisolano, J. L., et al., Proc. Natl. Acad. Sci. USA. (2003)
100:9506-9511.

[0313] In one embodiment, compositions and methods provided herein are
effective to modulate the activity of PDGFR. In other embodiments,
compositions and methods provided herein are effective to selectively
modulate the activity of PDGFR.

[0314] FLT-3

[0315] FLT3 kinase is a tyrosine kinase receptor involved in the
regulation and stimulation of cellular proliferation. See e.g., Gilliland
et al., Blood 100: 1532-42 (2002). The FLT3 kinase is a member of the
class III receptor tyrosine kinase (RTKIII) receptor family and belongs
to the same subfamily of tyrosine kinases as c-kit, c-fms, and the
platelet-derived growth factor .alpha. and .beta. receptors. See e.g.,
Lyman et al., FLT3 Ligand in THE CYTOKINE HANDBOOK 989 (Thomson et al.,
eds. 4th Ed.) (2003). The FLT3 kinase has five immunoglobulin-like
domains in its extracellular region as well as an insert region of 75-100
amino acids in the middle of its cytoplasmic domain. FLT3 kinase is
activated upon the binding of the FLT3 ligand, which causes receptor
dimerization. Dimerization of the FLT3 kinase by FLT3 ligand activates
the intracellular kinase activity as well as a cascade of downstream
substrates including Stat5, Ras, phosphatidylinositol-3-kinase (PI3K),
PLC.gamma., Erk2, Akt, MAPK, SHC, SHP2, and SHIP. See e.g., Rosnet et
al., Acta Haematol. 95:218 (1996); Hayakawa et al., Oncogene 19:624
(2000); Mizuki et al., Blood 96:3907 (2000); and Gilliand et al., Curr.
Opin. Hematol. 9:274-81 (2002). Both membrane-bound and soluble FLT3
ligand bind, dimerize, and subsequently activate the FLT3 kinase.

[0318] FLT3 kinase mutations associated with hematologic malignancies are
activating mutations. In other words, the FLT3 kinase is constitutively
activated without the need for binding and dimerization by FLT3 ligand,
and therefore stimulates the cell to grow continuously.

[0320] In some embodiments, the kinase is a class III receptor tyrosine
kinase (RTKIII). In other embodiments, the kinase is a tyrosine kinase
receptor intimately involved in the regulation and stimulation of
cellular proliferation. In still other embodiments, the kinase is a
fms-like tyrosine kinase 3 receptor (FLT-3 kinase). In this context,
inhibition and reduction of the activity of FLT-3 kinase refers to a
lower level of measured activity relative to a control experiment in
which the protein, cell, or subject is not treated with the test
compound, whereas an increase in the activity of FLT-3 kinase refers to a
higher level of measured activity relative to a control experiment. In
particular embodiments, the reduction or increase is at least 10%. One of
skill in the art will appreciate that reduction or increase in the
activity of FLT-3 kinase of at least 20%, 50%, 75%, 90% or 100% or any
integer between 10% and 100% may be preferred for particular
applications.

[0321] Compounds provided herein are useful in treating conditions
characterized by inappropriate FLT3 activity such as proliferative
disorders. FLT3 activity includes, but is not limited to, enhanced FLT3
activity resulting from increased or de novo expression of FLT3 in cells,
increased FLT3 expression or activity, and FLT3 mutations resulting in
constitutive activation. The existence of inappropriate or abnormal FLT3
ligand and FLT3 levels or activity can be determined using well known
methods in the art. For example, abnormally high FLT3 levels can be
determined using commercially available ELISA kits. FLT3 levels can be
determined using flow cytometric analysis, immunohistochemical analysis,
and in situ hybridization techniques.

[0322] An inappropriate activation of the FLT3 can be determined by an
increase in one or more of the activities occurring subsequent to FLT3
binding: (1) phosphorylation or autophosphorylation of FLT3; (2)
phosphorylation of a FLT3 substrate, e.g., Stat5, Ras; (3) activation of
a related complex, e.g., PI3K; (4) activation of an adaptor molecule; and
(5) cellular proliferation. These activities are readily measured by well
known methods in the art.

[0323] Formulations

[0324] The compounds described herein can be used to prepare a medicament,
such as by formulation into pharmaceutical compositions for
administration to a subject using techniques generally known in the art.
A summary of such pharmaceutical compositions may be found, for example,
in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.
The compounds of the invention can be used singly or as components of
mixtures. Preferred forms of the compounds are those for systemic
administration as well as those for topical or transdermal
administration. Formulations designed for timed release are also within
the scope of the invention. Formulation in unit dosage form is also
preferred for the practice of the invention.

[0325] In unit dosage form, the formulation is divided into unit doses
containing appropriate quantities of one or more compounds. The unit
dosage may be in the form of a package containing discrete quantities of
the formulation. Non-limiting examples are packeted tablets or capsules,
and powders in vials or ampoules.

[0326] The compounds described herein may be labeled isotopically (e.g.
with a radioisotope) or by any other means, including, but not limited
to, the use of chromophores or fluorescent moieties, bioluminescent
labels, or chemiluminescent labels. The compositions may be in
conventional forms, either as liquid solutions or suspensions, solid
forms suitable for solution or suspension in a liquid prior to use, or as
emulsions. Suitable excipients or carriers are, for example, water,
saline, dextrose, glycerol, alcohols, aloe vera gel, allantoin, glycerin,
vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl
propionate, and the like. Of course, these compositions may also contain
minor amounts of nontoxic, auxiliary substances, such as wetting or
emulsifying agents, pH buffering agents, and so forth.

[0327] Methods for the preparation of compositions comprising the
compounds described herein include formulating the derivatives with one
or more inert, pharmaceutically acceptable carriers to form either a
solid or liquid. Solid compositions include, but are not limited to,
powders, tablets, dispersible granules, capsules, cachets, and
suppositories. Liquid compositions include solutions in which a compound
is dissolved, emulsions comprising a compound, or a solution containing
liposomes, micelles, or nanoparticles comprising a compound as disclosed
herein.

[0328] A carrier of the invention can be one or more substances which also
serve to act as a diluent, flavoring agent, solubilizer, lubricant,
suspending agent, binder, or tablet disintegrating agent. A carrier can
also be an encapsulating material.

[0329] In powder forms of the invention's compositions, the carrier is
preferably a finely divided solid in powder form which is interdispersed
as a mixture with a finely divided powder from of one or more compound.
In tablet forms of the compositions, one or more compounds is intermixed
with a carrier with appropriate binding properties in suitable
proportions followed by compaction into the shape and size desired.
Powder and tablet form compositions preferably contain between about 5 to
about 70% by weight of one or more compound. Carriers that may be used in
the practice of the invention include, but are not limited to, magnesium
carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin,
starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a
low-melting wax, cocoa butter, and the like.

[0330] The compounds of the invention may also be encapsulated or
microencapsulated by an encapsulating material, which may thus serve as a
carrier, to provide a capsule in which the derivatives, with or without
other carriers, is surrounded by the encapsulating material. In an
analogous manner, cachets comprising one or more compounds are also
provided by the instant invention. Tablet, powder, capsule, and cachet
forms of the invention can be formulated as single or unit dosage forms
suitable for administration, optionally conducted orally.

[0331] In suppository forms of the compositions, a low-melting wax such
as, but not limited to, a mixture of fatty acid glycerides, optionally in
combination with cocoa butter is first melted. One or more compounds are
then dispersed into the melted material by, as a non-limiting example,
stirring. The non-solid mixture is then placed into molds as desired and
allowed to cool and solidify.

[0332] Non-limiting compositions in liquid form include solutions suitable
for oral or parenteral administration, as well as suspensions and
emulsions suitable for oral administration. Sterile aqueous based
solutions of one or more compounds, optionally in the presence of an
agent to increase solubility of the derivative(s), are also provided.
Non-limiting examples of sterile solutions include those comprising
water, ethanol, and/or propylene glycol in forms suitable for parenteral
administration. A sterile solution of the invention may be prepared by
dissolving one or more compounds in a desired solvent followed by
sterilization, such as by filtration through a sterilizing membrane
filter as a non-limiting example. In another embodiment, one or more
compounds are dissolved into a previously sterilized solvent under
sterile conditions.

[0333] A water based solution suitable for oral administration can be
prepared by dissolving one or more compounds in water and adding suitable
flavoring agents, coloring agents, stabilizers, and thickening agents as
desired. Water based suspensions for oral use can be made by dispersing
one or more compounds in water together with a viscous material such as,
but not limited to, natural or synthetic gums, resins, methyl cellulose,
sodium carboxymethyl cellulose, polyvinylpyrrolidone, and other
suspending agents known to the pharmaceutical field.

[0334] In therapeutic use, the compounds of the invention are administered
to a subject at dosage levels of from about 0.5 mg/kg to about 8.0 mg/kg
of body weight per day. For example, a human subject of approximately 70
kg, this is a dosage of from 35 mg to 560 mg per day. Such dosages,
however, may be altered depending on a number of variables, not limited
to the activity of the compound used, the condition to be treated, the
mode of administration, the requirements of the individual subject, the
severity of the condition being treated, and the judgment of the
practitioner.

[0335] The foregoing ranges are merely suggestive, as the number of
variables in regard to an individual treatment regime is large, and
considerable excursions from these recommended values are not uncommon.

[0336] Methods of Use

[0337] By modulating kinase activity, the compounds disclosed herein can
be used to treat a variety of diseases. Suitable conditions characterized
by undesirable protein-kinase activity can be treated by the compounds
presented herein. As used herein, the term "condition" refers to a
disease, disorder, or related symptom where inappropriate kinase activity
is present. In some embodiments, these conditions are characterized by
aggressive neovasculaturization including tumors, especially acute
myelogenous leukemia (AML), B-precursor cell acute lymphoblastic
leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic
leukemias, and chronic myelogenous leukemias (CMLs). In some embodiments,
a FLT3 modulating compounds may be used to treat tumors. The ability of
compounds that inhibit FLT3 kinase activity to treat tumors has been
established. Compounds having this property include SU5416 (Sugen),
PKC412 (Novartis), GTP-14564 and CT53518 (Millennium). See e.g., Giles et
al., Blood 102:795-801 (2003); Weisberg et al., Cancer Cell 1:433-43
(2002); Murata et al., J. Biol. Chem. 278:32892-98 (2003); and Kelly et
al., Cancer Cell 1:421-32 (2002).

[0338] Compounds presented herein are useful in the treatment of a variety
of biologically aberrant conditions or disorders related to tyrosine
kinase signal transduction. Such disorders pertain to abnormal cell
proliferation, differentiation, and/or metabolism. Abnormal cell
proliferation may result in a wide array of diseases, including the
development of neoplasia such as carcinoma, sarcoma, leukemia,
glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and
diabetic retinopathy (or other disorders related to uncontrolled
angiogenesis and/or vasculogenesis).

[0339] In various embodiments, compounds presented herein regulate,
modulate, and/or inhibit disorders associated with abnormal cell
proliferation by affecting the enzymatic activity of one or more tyrosine
kinases and interfering with the signal transduced by said kinase. More
particularly, the present invention is directed to compounds which
regulate, modulate said kinase mediated signal transduction pathways as a
therapeutic approach to cure leukemia and many kinds of solid tumors,
including but not limited to carcinoma, sarcoma, erythroblastoma,
glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma.
Indications may include, but are not limited to brain cancers, bladder
cancers, ovarian cancers, gastric cancers, pancreas cancers, colon
cancers, blood cancers, lung cancers and bone cancers.

[0340] In other embodiments, compounds herein are useful in the treatment
of cell proliferative disorders including cancers, blood vessel
proliferative disorders, fibrotic disorders, and mesangial cell
proliferative disorders. Blood vessel proliferation disorders refer to
angiogenic and vasculogenic disorders generally resulting in abnormal
proliferation of blood vessels. The formation and spreading of blood
vessels, or vasculogenesis and angiogenesis, respectively, play important
roles in a variety of physiological processes such as embryonic
development, corpus luteum formation, wound healing and organ
regeneration. They also play a pivotal role in cancer development. Other
examples of blood vessel proliferation disorders include arthritis, where
new capillary blood vessels invade the joint and destroy cartilage, and
ocular diseases, like diabetic retinopathy, where new capillaries in the
retina invade the vitreous, bleed and cause blindness. Conversely,
disorders related to the shrinkage, contraction or closing of blood
vessels, such as restenosis, are also implicated.

[0341] Fibrotic disorders refer to the abnormal formation of extracellular
matrix. Examples of fibrotic disorders include hepatic cirrhosis and
mesangial cell proliferative disorders. Hepatic cirrhosis is
characterized by the increase in extracellular matrix constituents
resulting in the formation of a hepatic scar. Hepatic cirrhosis can cause
diseases such as cirrhosis of the liver. An increased extracellular
matrix resulting in a hepatic scar can also be caused by viral infection
such as hepatitis. Lipocytes appear to play a major role in hepatic
cirrhosis. Other fibrotic disorders implicated include atherosclerosis
(see, below).

[0342] Mesangial cell proliferative disorders refer to disorders brought
about by abnormal proliferation of mesangial cells. Mesangial
proliferative disorders include various human renal diseases, such as
glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,
thrombotic microangiopathy syndromes, transplant rejection, and
glomerulopathies. The cell proliferative disorders which are indications
of the present invention are not necessarily independent. For example,
fibrotic disorders may be related to, or overlap, with blood vessel
proliferative disorders. For example, atherosclerosis results, in part,
in the abnormal formation of fibrous tissue within blood vessels.

[0343] Compounds of the invention can be administered to a subject upon
determination of the subject as having a disease or unwanted condition
that would benefit by treatment with said derivative. The determination
can be made by medical or clinical personnel as part of a diagnosis of a
disease or condition in a subject. Non-limiting examples include
determination of a risk of acute myelogenous leukemia (AML), B-precursor
cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell
acute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs).

[0344] The methods of the invention can comprise the administration of an
effective amount of one or more compounds as disclosed herein, optionally
in combination with one or more other active agents for the treatment of
a disease or unwanted condition as disclosed herein. The subject is
preferably human, and repeated administration over time is within the
scope of the present invention.

[0345] The present invention thus also provides compounds described above
and their salts or solvates and pharmaceutically acceptable salts or
solvates thereof for use in the prevention or treatment of disorders
mediated by aberrant protein tyrosine kinase activity such as human
malignancies and the other disorders mentioned above. The compounds of
the present invention are especially useful for the treatment of
disorders caused by aberrant kinase activity such as breast, ovarian,
gastric, pancreatic, non-small cell lung, bladder, head and neck cancers,
and psoriasis. The cancers include hematologic cancers, for example,
acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic
leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic
leukemias, and chronic myelogenous leukemias (CMLs).

[0346] A further aspect of the invention provides a method of treatment of
a human or animal subject suffering from a disorder mediated by aberrant
protein tyrosine kinase activity, including susceptible malignancies,
which comprises administering to the subject an effective amount of a
compound described above or a pharmaceutically acceptable salt or solvate
thereof.

[0350] A further aspect of the present invention provides the use of a
compound described above, or a pharmaceutically acceptable salt thereof,
in the preparation of a medicament for the treatment of psoriasis.

[0351] As one of skill in the art will recognize, the compounds can be
administered before, during or after the occurrence of a condition or a
disease, and the timing of administering the composition containing a
compound can vary. Thus, for example, the compounds can be used as a
prophylactic and can be administered continuously to subjects with a
propensity to conditions and diseases in order to prevent the occurrence
of the disorder. The compounds and compositions can be administered to a
subject during or as soon as possible after the onset of the symptoms.
The administration of the compounds can be initiated within the first 48
hours of the onset of the symptoms, preferably within the first 48 hours
of the onset of the symptoms, more preferably within the first 6 hours of
the onset of the symptoms, and most preferably within 3 hours of the
onset of the symptoms. The initial administration can be via any route
practical, such as, for example, an intravenous injection, a bolus
injection, infusion over 5 min. to about 5 hours, a pill, a capsule,
transdermal patch, buccal delivery, and the like, or a combination
thereof. A compound is preferably administered as soon as is practicable
after the onset of a condition or a disease is detected or suspected, and
for a length of time necessary for the treatment of the disease, such as,
for example, from about 1 month to about 3 months. As one of skill in the
art will recognize, the length of treatment can vary for each subject,
and the length can be determined using the known criteria. For example,
the compound or a formulation containing the compound can be administered
for at least 2 weeks, preferably about 1 month to about 5 years, and more
preferably from about 1 month to about 3 years.

[0352] Kits/Articles of Manufacture

[0353] For use in the therapeutic applications described herein, kits and
articles of manufacture are also within the scope of the invention. Such
kits can comprise a carrier, package, or container that is
compartmentalized to receive one or more containers such as vials, tubes,
and the like, each of the container(s) comprising one of the separate
elements to be used in a method of the invention. Suitable containers
include, for example, bottles, vials, syringes, and test tubes. The
containers can be formed from a variety of materials such as glass or
plastic.

[0354] For example, the container(s) can comprise one or more compounds of
the invention, optionally in a composition or in combination with another
agent as disclosed herein. The container(s) optionally have a sterile
access port (for example the container can be an intravenous solution bag
or a vial having a stopper pierceable by a hypodermic injection needle).
Such kits optionally comprising a compound with an identifying
description or label or instructions relating to its use in the methods
of the present invention.

[0355] A kit of the invention will typically may comprise one or more
additional containers, each with one or more of various materials (such
as reagents, optionally in concentrated form, and/or devices) desirable
from a commercial and user standpoint for use of a compound of the
invention. Non-limiting examples of such materials include, but not
limited to, buffers, diluents, filters, needles, syringes; carrier,
package, container, vial and/or tube labels listing contents and/or
instructions for use, and package inserts with instructions for use. A
set of instructions will also typically be included.

[0356] A label can be on or associated with the container. A label can be
on a container when letters, numbers or other characters forming the
label are attached, molded or etched into the container itself; a label
can be associated with a container when it is present within a receptacle
or carrier that also holds the container, e.g., as a package insert. A
label can be used to indicate that the contents are to be used for a
specific therapeutic application. The label can also indicate directions
for use of the contents, such as in the methods described herein.

[0357] The terms "kit" and "article of manufacture" may be used as
synonyms.

EXAMPLES

[0358] The present invention is further illustrated by the following
examples, which should not be construed as limiting in any way. The
experimental procedures to generate the data shown are discussed in more
detail below. For all formulations herein, multiple doses may be
proportionally compounded as is known in the art.

[0359] The invention has been described in an illustrative manner, and it
is to be understood that the terminology used is intended to be in the
nature of description rather than of limitation. Thus, it will be
appreciated by those of skill in the art that conditions such as choice
of solvent, temperature of reaction, volumes, reaction time may vary
while still producing the desired compounds. In addition, one of skill in
the art will also appreciate that many of the reagents provided in the
following examples may be substituted with other suitable reagents. See,
e.g., Smith & March, Advanced Organic Chemistry, 5.sup.th ed. (2001).

Example A

Synthesis of Isoxazole-Amides

[0360] Compounds A1 through A240 are synthesized by methods known in the
art or described herein. The structures are shown below in Table A:

[0362] In a 40 mL vial, 1 mL of thionyl chloride was added to 0.2 mmol
para-substituted phenylacetic acid. The vial was capped and stirred at
80.degree. C. for approximately three hours. The completion of the
reaction was checked by TLC. The excess thionyl chloride was removed in
vacuo. The residue was dissolved in dichloromethane and added to a
mixture of 3-tert-butyl-isoxazol-5-ylamine (0.2 mmol) and DIEA (0.2
mmol). The reaction was stirred overnight at 45.degree. C. The solvent
was removed under vacuum and the product was purified by HPLC.

[0364] (4-Benzyloxy-phenyl)-acetic acid (50 mg, 0.2 mmol, 1 eq) was
stirred with 1 mL of thionyl chloride at 80.degree. C. for approximately
three hours. The completion of the reaction was checked by TLC. Excess
thionyl chloride was removed in vacuo, the residue was dissolved in
dichloromethane and added to a mixture of 3-tert-butyl-isoxazol-5-ylamine
(28 mg, 0.2 mmol, 1 eq) and DIEA (35 .mu.L, 0.2 mmol, 1 eq). The reaction
was stirred overnight at 45.degree. C. The solvent was removed and the
product purified by HPLC. Yield: 42 mg (57%), LC/MS [MH.sup.+] 365.

[0365] Compounds B2 through B16 were synthesized in a manner analogous to
Compound B1 using similar starting materials and reagents. The structures
are shown below in Table B:

[0373] In a vial thionyl chloride was added to a para-substituted
phenylacetic acid. The vial was capped and stirred at 80.degree. C. for
approximately three hours. The completion of the reaction was checked by
TLC, and the excess thionyl chloride removed in vacuo. The residue was
dissolved in dichloromethane and added to a mixture
5-tert-butyl-isoxazol-3-ylamine and DIEA. The reaction was stirred
overnight at 45.degree. C. The solvent was removed under vacuum and the
product was purified by HPLC. 345

[0374] For the case of R=NO.sub.2, reduction to the amine was carried out
prior to reaction with an activated carboxylic acid. 1.5 gm of
1-(5-tert-butyl-isoxazol-3-yl)-3-(4-nitro-phenyl)-amide was dissolved in
50 ml THF and 0.1 g of 10% Pd/C is added. The solution was stirred under
hydrogen at 50 psi. for 24 hours then filtered through a Celite pad. The
organic solvent was evaporated under vacuum and the resulting residue was
triturated with ethyl acetate. 346

[0375] 1 equivalent of the carboxylic acid and 1.1 equivalent of CDI were
dissolved in dry DMF and stirred at 40.degree. C. for 2 h, then 1
equivalent of the substituted aniline was added. The reaction mixture was
stirred at 40.degree. C. overnight and the final product was purified by
preparative HPLC. 347

[0376] Alternatively, 1 equivalent of the carboxylic acid and 1.1
equivalent of thionyl chloride were heated in a sealed tube at 50 C for 3
h. The excess thionyl chloride was evaporated, 1 equivalent of aniline in
DMF was added, and the solution stirred at room temperature for 8 h. The
final product was purified by preparative HPLC.

[0377] Compounds F1 through F5 are synthesized in a manner analogous to
those shown above using similar starting materials and reagents. The
structures are shown below in Table F:

[0379] Methods for measuring binding affinities for interactions between
small molecules and kinases including FLT3, c-KIT, ABL(T334I) [a.k.a.
ABL(T315I)], VEGFR2 (a.k.a. KDR), and EGFR are described in detail in
U.S. application Ser. No. 10/873,835, which is incorporated by reference
herein in its entirety. Components of the assays include human kinases
expressed as fusions to T7 bacteriophage particles and immobilized
ligands that bind to the ATP site of the kinases. For the assay,
phage-displayed kinases and immobilized ATP site ligands are combined
with the compound to be tested. If the test compound binds the kinase it
competes with the immobilized ligand and prevents binding to the solid
support. If the compound does not bind the kinase, phage-displayed
proteins are free to bind to the solid support through the interaction
between the kinase and the immobilized ligand. The results are read out
by quantitating the amount of fusion protein bound to the solid support,
which is accomplished by either traditional phage plaque assays or by
quantitative PCR (qPCR) using the phage genome as a template. To
determine the affinity of the interactions between a test molecule and a
kinase, the amount of phage-displayed kinase bound to the solid support
is quantitated as a function of test compound concentration. The
concentration of test molecule that reduces the number of phage bound to
the solid support by 50% is equal to the K.sub.d for the interaction
between the kinase and the test molecule. Typically, data are collected
for twelve concentrations of test compound and, the resultant binding
curve is fit to a non-cooperative binding isotherm to calculate K.sub.d.

[0380] Compound F2 was tested against MKNK2 using the procedure outlined
above and showed activity towards the target of less than 50 nM.

[0381] All references cited herein, including patents, patent
applications, and publications, are herby incorporated by reference in
their entireties, whether previously specifically incorporated or not.

[0382] Having now fully described this invention, it will be appreciated
by those skilled in the art that the same can be performed within a wide
range of equivalent parameters, concentrations, and conditions without
departing from the spirit and scope of the invention and without undue
experimentation.

[0383] While this invention has been described in connection with specific
embodiments thereof, it will be understood that it is capable of further
modifications. This application is intended to cover any variations,
uses, or adaptations of the invention following, in general, the
principles of the invention and including such departures from the
present disclosure as come within known or customary practice within the
art to which the invention pertains and as may be applied to the
essential features hereinbefore set forth.